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23 September 2023

Interaction of Proteins Involved in Neuronal Proteinopathies

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1
Laboratory of Amyloid Biology, St. Petersburg State University, 199034 St. Petersburg, Russia
2
V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, 192019 St. Petersburg, Russia
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Authors to whom correspondence should be addressed.
Life2023, 13(10), 1954;https://doi.org/10.3390/life13101954
This article belongs to the Section Physiology and Pathology
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Abstract

Proteinopathy is characterized by the accumulation of aggregates of a specific protein in a target organ, tissue, or cell. The aggregation of the same protein can cause different pathologies as single protein can adopt various amyloidogenic, disease-specific conformations. The conformation governs the interaction of amyloid aggregates with other proteins that are prone to misfolding and, thus, determines disease-specific spectrum of concomitant pathologies. In this regard, a detailed description of amyloid protein conformation as well as spectrum of its interaction with other proteins become a key point for drafting of precise description of the disease. The majority of clinical cases of neuronal proteinopathies is caused by the aggregation of rather limited range of amyloidogenic proteins. Here, we provided the characterization of pathologies, related to the aggregation of amyloid β peptide, tau protein, α-synuclein, TDP-43, and amylin, giving a short description of pathologies themselves, recent advances in elucidation of misfolded protein conformation, with emphasis on those protein aggregates extracted from biological samples, what is known about the interaction of this proteins, and the influence of this interaction on the progression of underlying disease and comorbidities.

1. Introduction

Amyloid protein aggregation is the cause of a number of incurable and lethal diseases commonly names as amyloidoses or proteinopathies. In humans, more than 50 proteins and peptides prone to aggregation and even larger number of pathologies related to protein amyloidization have been discovered [1]. Despite this diversity, in case of neurodegenerative proteinopathies, nearly all of them can be described by the presence of mostly one of four protein aggregates—amyloid β-peptide (Aβ), τ-protein (tau), α-synuclein (α-Syn), and TAR DNA-binding protein 43 (transactive response DNA-binding protein 43 kDa, or TDP-43)—with morphology and distribution specific for each pathology [2]. Extracellular Aβ plaques (senile plaques) and cytoplasmic aggregates of phosphorylated tau (neurofibrillary tangles–NFTs and neuropil threads–NTs) are characteristic features of Alzheimer’s disease (AD) [3,4]. Various forms of tauopathies (Pick’s disease—PiD, corticobasal degeneration—CBD, progressive supranuclear palsy—PSP, argyrophilic grain disease—AGD, primary age-related tauopathy—PART, and neurofibrillary tangle-predominant dementia) commonly named as frontotemporal lobar degeneration with tau pathology (FTLD-tau) are characterized by cytoplasmic aggregates of phosphorylated tau [5,6]. The deposits of aggregated tau are different in morphology and they are localized in neuronal and glial cells in distinct parts of the brain depending on pathology [7]. Similarly, neuronal cytoplasmic α-Syn aggregates in forms of Lewy bodies (LB) and Lewy neurites (LN) are a neuropathological hallmark of Lewy body diseases (LBDs) that covers Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB). PD and DLB differs by the location of where α-Syn aggregation begins and direction where the pathology spread [8]. Multiply system atrophy (MSA) is characterized by filamentous α-Syn inclusions in olygodendrocytes with smaller amount of aggregated α-Syn also presented in neuronal cells [9]. Intracellular aggregates of phosphorylated TDP-43 in nuclei and cytoplasm of neurons and glial cells cause FTLD-TDP [10] and certain forms of amyotrophic lateral sclerosis (ALS) [11]. Taking into account similarities in genetic background, pathological hallmark, and clinical features of FTLD and ALS, they are frequently considered to be part of a common ALS-FTLD disease continuum [12].
As mentioned above, aggregation of the same protein can cause different pathologies. This phenomenon can be explained by the ability of amyloidogenic proteins to adopt various amyloid, disease-specific conformations. This conformation governs the interaction of amyloid aggregates with other proteins that are prone to aggregation and thus can determine disease-specific spectrum of concomitant pathologies. Co-pathologies can significantly increase the severity of underlying disease and establishing the range of possible co-pathologies is of extreme importance for setting up the correct treatment plan. In this regard, the detailed description of amyloid protein conformation as well as spectrum of its interaction with other proteins that are prone to aggregation become a key point for drafting of precise description of any protein misfolding disease.
In this review, we focused on what is known to date about the interaction between Aβ, tau, α-Syn, TDP-43, and amylin; recent advances in elucidation of atomic structure of amyloid assemblies formed by these proteins; and we discussed how this information can help in understanding of disease nature and developing new approaches for disease diagnostics and treatment. We also implemented into discussion peptide hormone amylin, also known as islet amyloid polypeptide (IAPP). This hormone is produced in pancreatic β-cells, and its amyloid aggregationin pancreas is a pathologic hallmark of type II diabetes mellitus (T2DM)—the most widely spread form of diabetes worldwide [13,14]. Despite amylin aggregation taking place out of nervous system, T2DM is proved to be a risk factor for various neuronal proteopathies, in particular, AD [15,16,17,18] and PD [19,20].

3. Co-Pathologies: The Influence of Protein Interaction and Disease-Specific Strains of Pathological Proteins

It is known that pure amyloidoses caused by the aggregation of a particular protein are quite rare and the disease is usually characterized by the presence of co-pathologies—deposits of other protein aggregates. In this case, symptomatic disease manifests, whereas co-pathologies may be either purely coincidental or have the influence on the disease development and clinical presentation [53]. For example, tau pathology may be present early in age without any clinical symptoms but be a prerequisite for the development of PART or AD. If another specific pathogenic event occurs such as Aβ aggregation, it may remain as co-pathology, or trigger to AD-related tau-pathology when Aβ aggregation exaggerates [53].
Several hypotheses exist to account for neurogenerative disease co-pathologies including ageing [137], cross-seeding of additional proteins by misfolded amyloidogenic protein [138,139] as well as genetic risk factors such as ApoE ε4 that increase the probability of AD manifestation [43] and probably can accelerate AD co-pathologies across other diseases. These hypotheses were tested by Robinson and co-workers [140], who investigated 766 autopsied samples representing a broad spectrum of neurodegenerative diseases, related to the aggregation of tau, Aβ, α-Syn, and TDP-43 as well as a group with minimal pathology, where no neuropathological disease was clinically diagnosed. Previous observation that tau and Aβ pathology occur with age independently of neurodegenerative diseases [36] was confirmed by the observation that both co-pathologies were common across tauopathies, synucleinopathies, TDP-43 proteinopathies as well as in minimal pathology group [140]. Groups with the highest age at death also had the highest frequencies of co-pathologies, thus confirming the hypothesis that proteinopathies are the part of normal ageing process. ApoE ε4 has been found to be a risk factor for co-pathologies independent on neurodegenerative disease [140].
Two sets of evidences support the proteopathic seeding hypothesis. First, in AD and LBD groups, but not in the case of TDP-43 proteinopathies, more severe primary pathology exhibited higher prevalence of co-pathologies. For example, the presence of multiply co-pathologies increased from 9% in intermediate AD to 25% in high AD and from 0% for brainstem LBD to 21% for neocortical LBD [140]. Second, different tauopathies and synucleinopathies displayed distinct pattern of co-pathologies and burdens. For example, TDP-43 co-pathology was not found in PiD, whereas it was found in 24% of CBD cases. Aβ and α-Syn co-pathologies were more frequent in PSP that in PiD and CBD [140]. Thereby, these results support the hypothesis that misfolded amyloidogenic protein can cross-seed the aggregation of additional proteins. Moreover, this suggests that cross-seeding ability may be determined by the distinct conformation (strain) of pathological protein [140].
The importance of protein interaction in co-pathologies appearance may be illustrated by the relationship between AD and T2DM—two the most prevalent protein misfolding disorders. The exact mechanism of risk association between T2DM and AD is not clear but there is a set of evidence in support of direct interaction between amylin and Aβ in vivo that will be discussed in details below. From this point of view, the investigation of the interaction of pathological proteins is of particular importance in terms of disease diagnostics, disease prognosis, and the development of therapeutic approaches for disease treatment. In the next paragraphs, we review what is known to date about interaction between amyloidogenic proteins and peptides reviewed here.

4. Pathological Protein Interaction

During last two decades, a number of studies have been conducted to investigate pathological proteins interaction in vitro, in vivo, and in silico, and studies related to Aβ occupy the central position. For example, in a recent review, the interaction of Aβ with 16 proteins that are prone to aggregation and not related to AD was described [141]. Increased interest to Aβ is determined first of all by its involvement into AD pathological process, and also by growing interest in the relationship between T2DM and AD, as this relationship may involve the direct interaction of Aβ and amylin. Therefore, in this section, we will begin from the discussion on the interaction of Aβ with other proteins.

4.1. Amyloid-β and Amylin Interaction

The interaction between amylin and Aβ peptide is probably the most widely investigated example of amyloidogenic protein interaction. The reason is that apart from T2DM and AD being the two most prevalent protein misfolding disorders, one of the diseases significantly increases the risk of the other [15,16,17,18]. The exact mechanism of risk association between T2DM and AD is not clear and several hypotheses were proposed such as altered insulin signaling, impaired glycose and lipid metabolism (metabolic syndrome), and reduced Aβ clearance capacity [142]. On the other hand, there is a set of evidence in support of direct interaction between amylin and Aβ. Amylin has been found to be co-deposited together with Aβ in senile plaques of AD patients [143] and aggregated Aβ and phosphorylated tau co-localized with amylin deposits in pancreas of T2DM patients [144].
The direct interaction of Aβ and amylin has been investigated by in vitro experiments [145,146,147,148], in vivo by the analysis in yeast [149] and Drosophila models [150], and in transgenic mice [139], as well as in silico, by mathematical modelling using amyloid conformations described for both peptides [129,130]. A sequence alignment of amylin and Aβ40 reveals 25% of sequence identity and 50% of sequence similarity (Figure 14A). Sequence identity and similarity become even higher when amylin region 20–29 a.a. residues that are critical for aggregation (corresponds to Aβ region 25–34 a.a. residues) are taken into account (rise to 44% and 66% identity and similarity, correspondingly). The implementation of S20G mutation into amylin sequence leads to further increase in identity and similarity of amylin and Aβ to 55% and 77%, correspondingly. Taking into account the aggregation capacity of both peptides and high sequence similarity and identity, the question rises if aggregation of one of these proteins can be seeded by the fibrils of another protein. O’Nullain and co-workers [145] showed that amylin monomers can be effectively seeded by both amylin and Aβ40 fibrils. On the other hand, Aβ40 monomers were poorly seeded by amylin aggregates exhibiting 50 times lower activity compared to Aβ40 fibrils [145]. The ability of amylin aggregates to seed Aβ aggregation had been further confirmed by other researchers [139,147] and resulting fibrils were shown to be composed of both peptides [139]. There are five hot regions for Aβ40-amylin interaction: three regions (19–22 a.a., 27–32 a.a. and 35–40 a.a.) in Aβ40 and two regions (8–18 a.a. and 22–28 a.a.) in amylin (see Figure 14A and [147]).
Figure 14. Interaction of amyloid β and amylin. (A) Sequence alignment of amylin and amyloid β (adopted from [145]). Long lines indicate identical residues, short lines indicate similarities. S20G mutation in amylin sequence is shown in red and increased identity of amylin and Aβ sequences as a result of S20G substitution is pointed out. Blue boxes display hot regions for Aβ-amylin interaction determined by Andreetto and co-workers [147]. Green box covers the sequences of undecapeptidic fragments of Aβ and S20G-amylin with the highest structural similarity [148]. (B–D) Structurally similar regions of Aβ and amylin fibrillar assemblies revealed by in silico superimposition of described Aβ and amylin structures stored in RCSB PDB [151]. The RCSB PDB reference code of the structures used in the experiment is mentioned. In model B, described by Röder and co-workers [129], the regions Aβ (16–24) and amylin (14–22) as well as Aβ (28–32) and amylin (23–27) possess similar structure. S20G substitution in amylin and E22G substitution in Aβ should result in analogous conformational consequences in the structure of both amylin and Aβ protofibrils. Model C, described by Cao and co-workers [130] recognize two regions of structural similarity between amylin and Aβ assemblies. In model D, developed by Cao and co-authors [136] the regions of Aβ and amylin responsible for cross-seeding were predicted.
Interestingly, amylin with N-methylated amide bonds at G24 and I26, i.e., inside the region critical for amylin aggregation and interaction with Aβ, can completely block aggregation of both Aβ40 and amylin in vitro and diminish the toxic effect of both peptide’s assemblies in cell culture [146].
Krotee and co-workers [148] investigated the structure of undecapeptides Aβ(24–34) and amylin(19–29) S20G that were derived from wild-type Aβ and S20G-amylin (Figure 14A) and found a high degree of structural similarity between backbone atoms of these fragments. Structural variants for assemblies composed of two peptides were calculated. Fibrils of both Aβ(24–34) and amylin(19–29) S20G induced amyloid formation through self- and cross-seeding and peptide inhibitors designed for one segment showed cross-efficacy for full-length Aβ and amylin and reduced cytotoxicity of both proteins in the cell culture [148].
Transgenic mice expressing both human amylin and APP exhibited exacerbated AD-like pathology compared with mice expressing human APP only or expressing human APP with streptozotocin-induced type 1 diabetes mellitus (T1DM) background [139]. Amylin colocalized with Aβ plaques in brain parenchyma deposits. The intracerebral injection of amylin aggregates led to more severe AD pathology and memory impairment in AD transgenic mice. Interestingly, amylin deposits in pancreas were substantially higher in animals overexpressing both human amylin and APP, relative to animals expressing human amylin only, suggesting that Aβ pathology may also contribute to pancreatic amylin aggregation [139]. Thereby, these data assume direct interaction of these peptides resulted in aggravation of the disease–AD in case of T2DM and, probably, vice versa. The interaction between human amylin and Aβ have been also investigated in a yeast model system [149]. Using FRET, the authors have shown that Aβ42 and amylin co-localize and interact physically in yeast.
Thus, an extensive set of evidence from in vitro and in vivo experiments supports the hypothesis of direct interaction of amylin and Aβ. Accumulated data on the peptides conformations in amyloid aggregates obtained by NMR, X-ray crystallography, EPR and especially recent advances in cryo-EM, where precise conformation of single assembly polymorph can be established, open wide perspectives in modelling of amyloid proteins interaction. Based on recently obtained cryo-EM structures aggregated wild-type- and S20G-amylin and cryo-EM structures of Aβ several models of possible amylin–Aβ interaction were developed (Figure 14B–D). The superimposition of amylin structures described by Cao and co-workers [130,136] and Röder and co-workers [129] with previously reported Aβ fibril structures revealed six different pairs of structurally similar regions in both peptides. Consensus epitopes are 14–33 a.a. residues for amylin and 16–31 a.a. residues for Aβ, which covers partially hot regions of Aβ40–amylin interaction described by Andreetto and co-workers [147] and include complete sequences of undecapeptides Aβ(24–34) and amylin(19–29) investigated by Krotee and co-workers [148].
The model proposed by Röder and co-workers [129] where S-fold of amylin is compared with LS-fold of Aβ (amylin 14–22 vs. Aβ 16–24) needs special attention. Ser20 of amylin and Glu22 of Aβ are located there in structurally similar positions. S20G substitution in amylin leads to dramatic changes in subunit structure of amylin amyloid protofibril [128]. It is suggested that the implementation of Arctic mutation (E22G) in Aβ might have analogous conformational consequences for subunit structure in Aβ protofibril [129]. The conformation of peptide in E22G-Aβ assembles has not been elucidated yet and, thus, the experimental testing of this hypothesis has to be carried out in the future.
To sum up, Aβ–amylin interaction has been extensively studied during the last two decades using various in vitro, in vivo, and in silico approaches. The capacity of amylin fibrils to seed Aβ aggregation as well as cross-seeding of amylin by Aβ assemblies have been approved experimentally. Significant progress has been reached in elucidation of near-atomic-resolution structures of amyloid fibrils of both peptides, mapping of interaction interface and analysis of the influence of this interaction on the development of T2DM and AD pathology. These results may be used for the development of new therapeutic agents for treatment of both AD and T2DM and the experimental approaches can be further applied for the analysis of interaction of other amyloidogenic proteins.

4.2. Amyloid-β and Tau Interaction

The interaction of Aβ and tau leads to the development of AD–unique dual proteinopathy that characterized by deposition of both proteins. Tau pathology can be met without co-existence of any Aβ pathology, for example, in PART [152]. Aβ plaques and NFTs begin in different brain regions and show different progression pattern [153], but in AD, they are converged, forming single pathologic lesion–neuritic plaque–intracellular tau inclusion together with extracellular aggregated Aβ, a distinct hallmark of AD [53]. Neuropathological data also indicate that Aβ pathology is necessary to spread tau pathology in AD out of the medial temporal lobe [153]. Tau pathology in the absence of Aβ pathology rarely exceeds NTF-Braak stage IV, while stages V/VI are present when Aβ pathology is also developed [36,152].
Pathogenic mutations in APP, PSEN1, and PSEN2 genes lead to an increased production of Aβ and to the development of familiar AD with accumulation of both aggregated Aβ and tau. On the other hand, mutations in MAPT gene lead to tauopathies, but not to AD [154]. Crossing transgenic mice which develop Aβ pathology with transgenic mice demonstrating tauopathy resulted in exacerbated tau pathology in progeny [155]. In mouse primary cell culture, the treatment by exogenous Aβ oligomers induced phosphorylation of tau in AD-specific manner and its mis-sorting into dendrites [156]. Thus, the development of Aβ pathology is a prerequisite for the development or aggravation of tau pathology and further development of AD.
The regions of interaction between tau and Aβ were determined [157]. The strongest binding of tau has been shown for three regions of Aβ42: 11–16, 27–32, and 37–42 a.a. residues, and interaction regions of tau located at multiply sites, especially in exons 7 and 9. The binding enhances the phosphorylation of tau by GSK-3β and promotes Aβ nucleation into aggregates. Phosphorylated tau loses the affinity to Aβ, which results in dissociation of the complex. Phosphorylation of T212, S214, S356, and S396 in tau completely blocked Aβ42 binding, phosphorylation of T217 and T231 decreased the binding significantly, whereas phosphorylation of T181, S202, and T205 had no effect [157]. Complexes of tau and Aβ were detected in soluble extracts from AD and control brain tissues and double immunostaining of AD brain tissue recognized phosphorylated tau and Aβ to form separate insoluble complexes within the same neurons and their processes [157]. The authors hypothesized that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble Aβ to soluble non-phosphorylated tau, thus promoting tau phosphorylation and Aβ nucleation [157]. This hypothesis explains the convergence in the development of tau and Aβ pathology as well as Aβ-stimulated aggravation of tau pathology in AD. It is also in accordance with the recent data on disease-specific strains of pathological tau. The interaction of Aβ and tau leads to the implementation of specific PTMs into tau, for instance, by the phosphorylation of Ser256 with GSK-3β in Aβ-tau complex. These specific PTMs may divert phosphorylated tau toward the aggregation in AD-specific amyloid conformation.

4.3. Amyloid-β and TDP-43 Interaction

TDP-43 pathology is detected in AD brains in 20–40% of AD cases [140,158] with higher prevalence of TPD-43 pathology in severe AD [140]. TDP-43 pathology has been shown to be associated with more extended brain atrophy and greater memory loss as well as with the severity of AD pathology, namely higher Braak NFT stages and Thal amyloid phases [159]. On the other hand, in case of ALS and FTLD-TDP, Aβ pathology was discovered in 36% and 42%, correspondingly, and severity of TDP-43-related disease did not correlate with the presence Aβ pathology [140].
A triple increase in full-length TDP-43 level has been found in brain cortex of late-stage AD patients relative to non-AD control [160]. Similar to the pathological changes seen in human AD brain, the lentiviral expression of Aβ42 in the rat motor cortex led to the increase in TDP-43 level, its phosphorylation and accumulation in cytosol. The injection of lentiviral parkin that stimulates intracellular Aβ42 clearance prevented TDP-43 pathology [160]. Lentiviral expression of α-Syn did not affect TDP-43 and parkin co-expression with Aβ42 did not affect the development of tau pathology. These results suggest that TDP-43 pathology is triggered specifically by elevated level of Aβ42 and by the mechanism independent on tau [160].
The overproduction of TDP-43 in cortex and hippocampus of APP/PS1 mouse that possesses mutant APP and PSEN1 genes increased abnormal tau aggregation and decreased Aβ plaque deposition with a simultaneous increase in endosomal/lysosomal APP localization [161]. Additionally, the elevation of TDP-43 level decreased the activity of calcineurin, a phosphatase for TDP-43, thus promoting the shift toward to TDP-43 phosphorylation [161]. Interestingly, knockout of TDP-43 in forebrain of APP/PS1 mouse also decreased Aβ plaque deposition, but led to neurodegeneration and accumulation of prefibrillar oligomeric Aβ assemblies [162]. Specific knockout of TDP-43 in microglia led to acceleration of its phagocytic activity that may explain decreased Aβ plaque formation due to enhanced Aβ clearance [163]. At the same time, microglial knockout of TDP-43 led to synaptic loss [163]. Thus, both elevation and decrease in TDP-43 level may contribute to AD pathological process by the influence to tau phosphorylation, Aβ aggregation state, Aβ clearance, and neurodegeneration.
Recombinant full-length TDP-43 inhibited in vitro Aβ fibrillization at initial and oligomeric stage. It was shown that TDP-43 binds Aβ through RBD domain(s), N-terminus of TDP-43 is critical for inhibition of Aβ fibrillization, while C-terminus is not necessary for Aβ-TDP-43 interaction [164]. The presence of TDP-43 fragments containing both N-terminus and RBD in the reaction mixture triggered Aβ aggregation from fibrillization to predominant formation of oligomers [164]. The intrahippocampal injection of TDP-43 led to increased level of Aβ oligomers, inflammation, and exacerbation of AD-like pathology [164]. At the same time, TDP-43 can form in vitro structurally stable spherical oligomers that can be recognized with an anti-amyloid oligomer-specific antibody [84]. These oligomers were capable of cross-seeding Aβ to form amyloid oligomers [84]. Such oligomers were extracted from the brain of transgenic TDP-43 mice and from the brain samples of AD-, ALS-, and FTLD-TDP patients [84,87]. In the brain of AD patients and of APP/PS1 mouse, TDP-43 oligomers mainly colocalized with intraneuronal Aβ and partly with amyloid plaque [164]. On the other hand, Aβ42 oligomers can seed recombinant TDP-43 protein and accelerate the formation of TDP-43 oligomers [165]. Importantly, Aβ42 fibril seeds were able to accelerate formation of Aβ42 fibrils, but not TDP-43 fibrils. Additionally, oligomeric structures composed of TDP-43 and Aβ or αSyn were shown to be present in AD-brain parenchyma and vasculature [165]. Similarly with tau-associated pathologies, when the pattern of tau pathology distribution is different between AD and other tauopathies, spreading of TDP-43 pathology in AD differs from that in FTLD and ALS [166,167] and detailed staging scheme for classifying TDP-43 pathology in AD has been recently developed [167].
To sum up, TDP-43 and Aβ can interact and this interaction has been confirmed in the experiments in vitro and in vivo. TDP-43 pathology may accompany AD and aggravate disease progression by the mechanism that may involve enhanced tau phosphorylation and Aβ oligomer production. On the other hand, Aβ and tau oligomers may affect TDP-43 subcellular distribution and aggregation state, thus governing the spreading of TDP-43 pathology in AD-specific manner.

4.4. Amyloid-β and α-Syn Interaction

Up to 60% of AD cases exhibit significant LB pathology in addition to Aβ plaques and NFT [140,168], whereas in a group with minimal pathology, it was recognized as being 10 times less frequent [140]. Across LBD patients, Aβ pathology prevalence was around 50% that was similar with aged control group with minimal pathology, except severe LBD cases with LB presented in neocortical region, where Aβ deposits were recognized in 80% of cases [140]. As levels of AD neuropathology increased, cerebral α-Syn scores were also higher, and the interval between the onset of motor and dementia symptoms as well as disease duration were shorter [169]. The most severe cases can be characterized as mixed AD/LB dementia since the severity of either AD or LB pathology alone would be sufficient for clinical dementia. In these cases, one pathology may be primary and drive neurodegeneration and the development of the other pathology as concomitant [169]. Tight overlapping of AD and LB pathologies suggests the possible interaction of Aβ and α-Syn.
Among transgenic mice with neuronal expression of Aβ, α-Syn, or both, doubly transgenic mice resembled the phenotype of LB variant of AD [170]. These mice were characterized by more extensive α-Syn neuronal pathology and developed severe learning, memory, and motor deficit earlier than α-Syn singly transgenic mice [170]. In vitro experiments showed that α-Syn can form oligomers and higher molecular weight aggregates in the presence of equimolar amount of Aβ and, thus, enhanced α-Syn accumulation in the brain and neuronal deficit in doubly transgenic mice was explained by the interaction of Aβ and α-Syn that promotes the aggregation of the later protein [170].
The capacity of these two proteins to interact has been studied in vitro using multidimensional NMR spectroscopy [171]. Aβ and α-Syn interacted in aqueous solution with SDS that mimic membrane environment, as was evident by the alteration of chemical shift of amide protons corresponding to a.a. residues 3–37 of Aβ40 and 10–140 of α-Syn [171]. In case of Aβ42, the interaction was non-specific and covered all the residues of the peptide [171]. It has been proposed that Aβ–α-Syn interaction take place at the surface of synaptic membrane, and it results in conformational changes of α-Syn that initiate its aggregation [171]. On the other hand, the modelling of the interaction between Aβ oligomers and oligomers formed by NAC region of α-Syn demonstrated that NAC oligomers induced formation of new β-strands in Aβ42, thus leading to new, more stable and compact cross-β structure of Aβ42 oligomers in heterologous assemblies [172].
It has been shown that Aβ and α-Syn are co-immunoprecipitated from the brain samples of AD/PD patients and transgenic mice [173]. Additionally, these proteins were able to form hybrid, ring-shaped pore-like oligomers [173]. HEK293 cell culture overproducing α-Syn displayed calcium influx consistent with the formation of ion channels after the exposure by exogenous Aβ [173], thus demonstrating a potential detrimental effect of Aβ–α-Syn interaction on cell membrane integrity. Ono and co-workers [174] showed that both fibrillar and oligomer seeds of Aβ can induce aggregation of αSyn and vice versa. α-Syn seeds were more potent than those of Aβ in seeding of both α-Syn and Aβ, and fibrillar assemblies of both proteins seeded the aggregation more effectively than oligomers [174]. The propensity of Aβ42 oligomers to seed α-Syn oligomerization in vitro has been confirmed later and α-Syn oligomers were histochemically detected in human AD brain samples [165]. Importantly, in that study, Aβ42 fibrils could not seed α-Syn aggregation in vitro and it was proposed that oligomer rather than fibrillar Aβ seeds act as a template for α-Syn and other proteins, namely PrP and TDP-43 [165].
To sum up, Aβ and α-Syn can interact and synergistically aggravate each other’s pathology in AD and LBD. For this reason, the interaction of Aβ and α-Syn is an important target for the development of novel therapeutic approaches for treatment of both AD and LBD.

4.5. Tau and α-Syn Interaction

The interaction of α-Syn and tau has been firstly described by Jensen and co-workers [175], who showed that α-Syn binds tau and stimulates tau phosphorylation by protein kinase A. It was proposed that α-Syn modulates the phosphorylation of soluble tau and thereby indirectly affects the stability of axonal microtubules [175]. At the same time, tau and α-Syn aggregated together in the same deposits [176,177,178,179]. Moreover, some inclusions were comprised of both proteins with almost complete spatial disparity [177].
Certain mutations of SNCA or MAPT gene were found to result in elevation of tau- or α-Syn pathology, correspondingly, giving additional evidence of possible α-Syn–tau interaction. For example, α-Syn mutation A53T that is known to increase aggregation propensity of α-Syn [180,181] results in widespread of both α-Syn and tau inclusions in the brain [177]. MAPT H1 haplotype was identified as genetic risk factor of PD [182] and DLB [183]. Additionally, a significant association with DLB and LBD was shown for point mutation A152T in tau [184].
Experiments in vitro displayed that α-Syn induced fibrillization of tau and that coincubation of α-Syn and tau synergistically promotes fibrillization of both proteins [185]. All six major tau isoforms were prone to aggregation in presence of α-Syn. Both proteins formed fibrils and most of them were homopolymers with only rare α-Syn-formed fibrils also displayed sporadic tau-immunoreactivity. Moreover, some fibrils were found to possess spatially separate domains with labeling by either αSyn, or tau antibodies, suggesting that these fibrils resulted from the end-to-end annealing of filaments formed entirely by either tau, or α-Syn [185]. The co-occurrence of α-Syn and tau inclusions were shown in single transgenic mice expressing human A53T α-Syn and in double transgenic mice expressing wild type α-Syn and P301L tau in oligodendrocytes. In both cases, apart from inclusions composed of tau or α-Syn alone, there were those formed by both proteins [185].
Despite cross-seeding of tau and α-Syn being clearly described, it was not uniformly reproduced in further studies [186]. This phenomenon was explained when two polymorphs (strains) of aggregated α-Syn with distinct propensity to seed aggregation of tau were isolated [187]. The assemblies of two polymorphs did not differ in morphology and in physio-chemical properties and represented almost the same pattern of proteolytic fragments after digestion by proteinase K [187]. Nevertheless, experiments with neuronal cell culture and transgenic mice displayed significant difference in biological activity between two polymorphs. Fibrils of the first polymorph were toxic for cell culture and induced extensive α-Syn pathology in the absence of any tau aggregation. Oppositely, fibrils of second polymorph had no negative impact on cell survival and induced aggregation of both α-Syn and tau with high proportion of co-localization. Similar results were obtained with transgenic mice [187]. Importantly, α-Syn assemblies prepared from N-terminal-truncated forms were incapable to seed tau; thus, N-terminal sequence (1–58 a.a.) appears to be necessary to form cross-seeding complement for α-Syn–tau interaction [187]. On the other hand, when α-Syn promotes tau phosphorylation by protein kinase A, C-terminus of α-Syn is involved into interaction [175]. Additionally, Guo and co-workers [187] showed, that pathological α-Syn derived from PD dementia and PD/AD dementia brain may be conformationally different. In the previous section, we described recent advances in elucidation of disease-specific conformation of pathological α-Syn but in correspondence to different diseases. This result suggests multiple amyloid conformations of the protein within one disease.
It has been also shown that tau can form SDS-resistant oligomers in vitro and oligomerization is synergistically enhanced by physiologically relevant concentrations of Al3+ and tau phosphorylation by GSK-3β [188]. Moreover, trivalent ions such as Al3+ and Fe3+, organic solvents and phosphorylation of tau facilitated co-oligomerization of tau with α-Syn as well as recruitment of α-Syn in pre-formed tau oligomers [188]. Co-oligomerization of amyloidogenic proteins that was also described for α-Syn–TDP-43, Aβ–α-Syn and Aβ–TDP-43 interaction [165,173] may reflect common pathological mechanism explaining cross-seeding phenomenon and coincidence of different pathologies in one disease.
To sum up, α-Syn and tau can interact in multiple ways. Soluble proteins can synergistically promote fibrillization of both proteins. α-Syn assemblies can seed aggregation of tau and seeding activity of α-Syn aggregates is determined by the conformation of α-Syn. Additionally, α-Syn and tau can form oligomers composed of both proteins, thus representing the features shown for interaction of other proteins.

4.6. Tau and TDP-43 Interaction

Among various tauopathies, TDP-43 inclusions were found in AD, CBD, and PSP, but not in PiD [79,140,189,190,191]. In AD, despite a subset of TDP-43-positive inclusions co-existing with NFTs in the same neurons, a double-immunofluorescent analysis assay did not show any co-localization of these structures [79,189]. In CBD, TDP-43-positive inclusions showed partial but not complete overlap with tau immunoreactivity [189]. In PSP, the co-localization existed, but it was region-specific and presented in amygdala, but not in hippocampal gyrus [190]. Also, immunoblotting demonstrated the appearance of smear corresponded to high molecular weight TDP-43 aggregates in the TDP-43-positive AD, CBD, and PSP cases [189,190].
It has been shown that tau can modulate cellular localization and oligomerization of TDP-43 [87]. Exogenous treatment of cell culture with soluble human recombinant tau oligomers increased the level of both phosphorylated and non-phosphorylated TDP-43 monomers in nucleus, as well as the amount of TDP-43 oligomers in cytoplasm. At the same time, tau oligomers induced redistribution of TDP-43 oligomers from low-molecular-weight (150 kDa) to high-molecular-weight fraction (>250 kDa). The overproduction of tau in cell culture did not affect TARDBP gene expression, but decreased of TDP-43 oligomers in the nucleus with a simultaneous increase in TDP-43 oligomers in the cytoplasm [87]. TDP-43 oligomers of various pathologic origin (AD, ALS and FTLD-TDP) extracted from the brain samples were able to seed aggregation of recombinant tau in vitro. Nevertheless, the treatment of aggregated tau with proteinase K and subsequent PAGE did not show any disease-specific profile of proteolytic fragments [87]. Despite the ability of TDP-43 oligomers to seed oligomerization of tau, immunofluorescent analysis revealed poor co-localization of TPD-43 oligomers and tau oligomers in brain tissues from AD patients [87].
To sum up, tau can modulate oligomerization state and cellular localization of TDP-43, whereas amyloid oligomers of TDP-43 can seed soluble tau in vitro. However, despite it being supposed that TDP-43 and tau may influence each other’s pathological progression [77], this preposition has to be more extensively checked. Additional studies are required to elucidate the relationship between tau and TDP-43.

4.7. Tau and Amylin Interaction

Tight interdependence between AD and T2DM discussed above in terms of Aβ and amylin interaction raises an additional question if diabetes may also affect the development or aggravation of tau pathology in AD and other tauopathies, and if tau and amylin may directly interact or not. Several studies displayed enhanced tau phosphorylation in the brain under T1DM [192,193,194,195,196,197] as well as under T2DM [192,196] condition. In the T1DM model, wild-type tau was hyperphosphorylated, but not aggregated, whereas P301L mutant tau formed massive NFTs [195]. AD-specific pathology developed in T2DM, but not in the T1DM model [193,194].
The mechanism of tau phosphorylation in diabetes involves altered insulin signaling as a result of insulin tolerance. Binding of insulin to insulin receptor activates Akt pathway that results in phosphorylation of GSK-3β kinase [198]. This kinase is able to phosphorylate tau and it is maintained inactive being phosphorylated. Insulin resistance leads to disruption of Akt pathway, dephosphorylation of GSK-3β, and hence, to its activation with subsequent hyperphosphorylation of tau [198]. Additionally, diabetes results in inhibition of brain protein phosphatase 2A that is capable of dephosphorylating tau at multiply residues [192].
El Khoury and co-workers [199] have analyzed more than 30 studies reporting brain tau phosphorylation in a mouse or rat model of T1DM and T2DM and found that insulin disfunction can promote tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia. Nevertheless, Zhang and co-workers [200] have recently reported accelerated aggregation of recombinant K18 tau fragment in vitro in the presence of soluble or fibrillar amylin. Compared with heparin-induced K18-tau fibrils, heterological fibrils differed in morphology, displayed altered profile of proteolytic fragments after PK digestion, and demonstrated enhanced seeding activity and cytotoxicity in vitro [200]. The intracerebral injection of synthetic amylin fibrils initiated tauopathy in the brain of tau-P301S transgenic mice [200]. Despite the shown possibility of amylin assemblies to seed tau aggregation in vitro and induce tau pathology in vivo [200], we are rather skeptical about the existence of such a mechanism in AD for two reasons. First of all, both T1DM and T2DM conditions similarly increased tau phosphorylation and this effect was mediated by kinase activity through impaired insulin signaling and hypothermia. Secondly, we did not find any published evidence on the association of T2DM with any of the tauopathies other than AD. Thus, we suppose that even if there is a direct interaction between tau and amylin, there is currently no information that such an interaction can influence the onset and development of tau-related pathologies.

4.8. α-Syn and TDP-43 Interaction

The evidence on the interaction between α-Syn and TDP-43 is restricted. The TDP-43 proteinopathies, both ALS and FLTD-TDP, demonstrated the elevation of α-Syn co-pathology with the severity of the main disease burden [140]. On the other hand, different synucleinopathies demonstrated differing prevalence of TDP-43 co-pathologies. In LBD, the prevalence of TDP-43 co-pathology increased with the severity of disease being close to zero among the patients with brainstem LBD and exceeding 20% among the group with neocortical LBD showing similar dynamics with the prevalence of Aβ co-pathology [140]. In an AD/LB dementia group of patients, TDP-43 co-pathology was more frequent than in pure LBD group, but less prevalent than among pure AD patients [201]. In MSA, the prevalence of TDP-43 pathology was higher than in the control group, but lower than in case of limbic or neocortical LBD [140].
α-Syn and TDP-43 can form oligomers composed of molecules of both proteins and the presence of these aggregates was shown in AD brain [165]. The presence of chimeric α-Syn–TDP-43 oligomers similar with those described for Aβ–α-Syn [173] and Aβ–TDP-43 [165] means that cross-seeding mechanism may exist for α-Syn–TDP-43 interaction. This may partially explain increased prevalence of TDP-43 co-pathology with growing severity of LBD. On the other hand, it may be also explained by simultaneous expansion of Aβ co-pathology and further Aβ-driven aggregation of TDP-43.
To sum up, the data on α-Syn–TDP-43 interaction collected to date are rather incomplete. Additional investigations have to be conducted to understand the nature of α-Syn–TDP-43 interaction and its possible influence on the development of α-Syn- or TDP-43-related proteinopathies as separate diseases or as co-pathologies.

4.9. α-Syn and Amylin Interaction

The data accumulated to date suggest that T2DM is associated with an increased risk of PD [19,20]. PD patients with dementia are two times more likely to have insulin resistance than patients with PD [202], suggesting diabetic symptoms may aggravate the progression of PD. Experiments in vitro displayed that whereas both amylin and α-Syn alone can form amyloids, mixing of amylin and α-Syn monomers results in coaggregation that is faster than either protein aggregates alone [203]. Human α-Syn monomers promoted human amylin, but not non-amyloidogenic rat amylin aggregation in vitro in dose-dependent manner and resulted assemblies were composed of both proteins, suggesting that under these conditions α-Syn and amylin form hybrid amyloid fibrils [204]. Interestingly, preformed seeds and fibrils of α-Syn were not able to promote amylin aggregation [204], whereas pre-formed amylin amyloid accelerated α-Syn fibrillization [203]. Importantly, in contrast to mature amylin, pro-amylin assemblies inhibited rather than promoted α-Syn aggregation [203]. The modelling of the interaction between amylin oligomers and oligomers formed by NAC fragment of α-Syn displayed that structural features of NAC core in NAC-amylin hetero-oligomers were not affected, whereas amylin oligomers acquired more stable conformation [205]. Similar stabilization was also described for Aβ involved into heterologous NAC-Aβ oligomers [170].
Cytoplasmic phosphorylated α-Syn deposits were found in pancreatic β-cells of patients with PD, DLB, and LBD [206], as well as in samples from patients with normal neuropathological examination, but suffering from T2DM [204,206]. Moreover, every sixth patients from control group (T2DM- and neuropathologically negative) were found to possess phosphorylated α-Syn inclusions in pancreas [206]. Additionally, α-Syn was found to be a component of amyloid extracted from pancreas of transgenic mice producing human amylin [204]. Tail-vein injection of α-Syn in mice expressing human amylin enhanced amylin deposition in pancreas, whereas amyloid formation in β-cells was reduced in transgenic mice expressing human amylin on Scna−/− background [204].
To sum up, there is strong evidence from in vitro, in vivo, and in silico studies that α-Syn and amylin can directly interact. Importantly, amylin deposits in the brain were found to be associated with T2DM [103], or with AD [143]. In the latter case, amylin and α-Syn are presented in amyloid plaques together with Aβ, but their colocalization seems to be determined by separate interaction of each protein with Aβ rather than by direct interaction of α-Syn and amylin. This preposition is supported by the fact that colocalization of α-Syn and amylin in the brain of patients with synucleinopathies has not been described yet. Thus, unlike Aβ–amylin interaction in AD and T2DM, where proteins can interact either in the brain or in the pancreas and deposits composed of Aβ and amylin can be present in both organs, α-Syn–amylin interaction seems to take place predominantly in islets β-cells.

4.10. TDP-43 and Amylin Interaction

The interaction of TDP-43 and amylin has not been analyzed yet. Nevertheless, recent studies discovered a negative relationship between T2DM and ALS [207,208,209,210]. This association was strong for non-insulin-dependent diabetes, but not for insulin-dependent diabetes [207]. It is known that both ALS and frontotemporal dementia are the factors decreasing the risk of cardiovascular diseases [210,211]. On the other hand, ALS patients are hypermetabolic and have impaired glucose tolerance [212,213]. In case of T2DM and ALS, one of the diseases may induce metabolic changes that compensate the risk of the another resulting in negative relationship between these pathologies.

5. Conclusions

The interaction between Aβ, tau, α-Syn, TDP-43, and amylin reviewed above are summarized in Table 1.
Table 1. Interaction of proteins involved in human amyloidoses.
Pathological protein aggregation seems to be the part of natural aging process, and the age when this process becomes recognizable depends on the protein itself, genetic background, and concomitant diseases and co-pathologies. The interaction of pathogenic proteins also plays an important role here, as they may lead to the development of a specific disease (for instance, interaction of Aβ and tau results in AD) or to the propagation of concomitant pathologies that aggravate the progression of the main disease (TDP-43 or α-Syn pathology in AD or Aβ pathology in PD), or to the appearance of another distinct disease in addition to the main one (AD at the background of T2DM and vice versa). This is why understanding of pathological proteins interaction is important for understanding of disease nature and for the prognosis of concomitant pathologies.
The interaction may lead to direct transfer of amyloid conformation from amyloid fibrils or oligomers of one protein to monomers of another protein, as it takes place in cross-seeding (interaction of Aβ and amylin, or Aβ and TDP-43). Alternatively, the interaction may promote templating-appearance of newly formed seeds (Aβ interacting with tau, α-Syn or amylin) or implementation of new PTMs such as phosphorylation that significantly increase aggregation propensity of the protein (tau interacting with Aβ or α-Syn). Moreover, both mechanisms can be potentially realized, as has been described for α-Syn–amylin, α-Syn–Tau, or α-Syn–Aβ interaction.
It is necessary to point out that pathological proteins are not necessarily interacting as was shown for tau–amylin and TDP-43–amylin. In this case, the development of concomitant pathologies may be due to physiological and biochemical disturbances appearing during main disease progression. These disturbances affect the risk of other disease progression. For example, both AD and T2DM are characterized by insulin and glucose tolerance, slowing down the metabolism, hypertension and, thus, one disease increases the risk of the another. On the other hand, ALS is characterized by the opposite physiological changes and in case of ALS and T2DM, the risks of one disease in case of the another is lower compared to the healthy control. Another example is the influence of T2DM on tau pathologies. Despite the recently described possibility of tau–amylin interaction, hypothermia that is the consequence of T2DM may make more significant contribution to tau phosphorylation and subsequent development of tau pathology.
To sum up, recently discovered disease-specific co-pathology profile supports the hypothesis about disease-specific amyloid polymorphs. This hypothesis has been strongly approved by the result of recent cryo-EM investigations where the structure of amyloid fibrils formed by various proteins, derived from in vitro reaction or from biological samples was elucidated with near-atomic resolution. Cryo-EM analysis revealed amazing diversity of amyloid conformations and fibril architectures that can be formed even by the same protein. Described structures allows clearly explain physio-chemical properties of fibrils such as affinity to amyloid-specific dyes, the influence of point mutations on exact amyloid conformation, thus explaining their pathogenic or protective role. The comparative analysis of structures formed by different proteins opens a perspective for elucidation of the regions responsible for protein interaction, as has been shown in case of the pair amylin–Aβ. Despite recent advances in elucidation of pathological protein interaction and the impact of this interaction to the progression of the main disease and development of co-pathologies, these data are rather incomplete. The data in Table 1 cover the results of in vitro, in vivo, and in silico experiments, where in vitro-formed assemblies and truncated forms of proteins were used in most cases. Taking into account observed structural differences between in vitro-formed and ex vivo-extracted protein assembles, further investigation should be focused on the elucidation of disease-specific amyloid conformation and analysis of their interactome. The establishment of clearer relationship between conformation and disease and conformation and co-pathologies should help in the development of novel conformation-specific diagnostic dyes as well as novel pharmaceutical substances that may affect the development disease and corresponding co-pathologies by modification of protein–protein interaction.

Author Contributions

Conceptualization, K.Y.K. and A.A.R.; validation, K.Y.K., O.A.M., A.E.Z., N.M.Z. and A.A.R.; formal analysis, K.Y.K. and A.A.R.; writing—original draft preparation K.Y.K.; writing—review and editing, O.A.M., A.E.Z., N.M.Z. and A.A.R.; visualization, K.Y.K.; supervision, A.A.R.; funding acquisition, A.A.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Russian Science Foundation, grant number 20-14-00148-П.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors acknowledge A.P. Galkin, J.V. Sopova, and P.A. Zykin for critical reading of the manuscript and valuable comments and Core Facility “Chromas” (Research Park, St. Petersburg State University) for technical assistance. The authors acknowledge the support from the St. Petersburg State University (project 94031363).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

a.a.Amino acid
AβAmyloid-β peptide
ADAlzheimer’s Disease
AGDArgyrophilic grain disease
ALSAmyotrophic lateral sclerosis
APPAmyloid precursor protein
BBBBlood–brain barrier
CAACerebral amyloid angiopathy
CBDCorticobasal degeneration
CPECarboxypeptidase E
CNSCentral nervous system
Cryo-EMCryo-electron microscopy
CSFCerebrospinal fluid
CTRCalcitonin receptor
DLBDementia with Lewi bodies
EPRElectron paramagnetic resonance spectroscopy
FRETFörster resonance energy transfer
FTLDFrontotemporal lobar degeneration
FTLD-TDPTDP-43 positive frontotemporal lobar degeneration
GCIGlial cytoplasmic inclusions
GRDGlycine-rich domain
GSKGlycogen synthase kinase
HEK293Human embryonic kidney 293 cells
IAPPIslet amyloid polypeptide
IDEInsulin-degrading enzyme
LBLewy bodies
LBDsLewy body diseases
LCOsLuminescent conjugated oligothiophenes
LNLewy neurites
MSAMultiply system atrophy
NACNon-amyloid component
NESNuclear export signal
NFTsNeurofibrillary tangles
NLSNuclear localization signal
NMRNuclear Magnetic Resonance spectroscopy
NTsNeuropil threads
PAGEPolyacrylamide gel electrophoresis
PARTPrimary age-related tauopathy
PAMPeptidylglycine alpha-amidating monooxygenase
PDParkinson’s disease
PDDParkinson’s disease dementia
PiDPick’s Disease
PMCAProtein Misfolding Cyclic Amplification technique
PKProteinase K
PrPPrion protein
PSPProgressive supranuclear palsy
PTMsPost-translational modifications
RAMP3Receptor activity modifying protein 3
RBDRNA-binding domain
RNPRibonuclear protein
α-Synα-Synuclein
SDSSodium dodecyl sulphate
SUMOSmall Ubiquitin-like Modifier
T1DMType I diabetes mellitus
T2DMType II diabetes mellitus
TDP-43Transactive response DNA-binding protein of 43 kDa
TMEM106BTransmembrane protein 106B

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