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Review

An Overview of Transgenic Mouse Models for the Study of Alzheimer’s Disease

by
Paula Alexandra Lopes
1,2,
Mafalda Soares Pádua
1,2 and
José L. Guil-Guerrero
3,*
1
CIISA—Centro de Investigação Interdisciplinar em Sanidade Animal, Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisboa, Portugal
2
Laboratório Associado para Ciência Animal e Veterinária (AL4AnimalS), Faculdade de Medicina Veterinária, Universidade de Lisboa, 1300-477 Lisboa, Portugal
3
Departamento de Tecnología de Alimentos, Universidad de Almería, 04120 Almería, Spain
*
Author to whom correspondence should be addressed.
J. Dement. Alzheimer's Dis. 2025, 2(1), 2; https://doi.org/10.3390/jdad2010002
Submission received: 9 November 2024 / Revised: 21 December 2024 / Accepted: 7 January 2025 / Published: 10 January 2025
Browse Figure
Versions Notes

Abstract

:
Alzheimer’s disease (AD) is the most common cause of dementia, and no cure is currently available. The β-amyloid cascade of AD and neurofibrillary tangles are the basis of the current understanding of AD pathogenesis, driving drug investigation and other discoveries. Up until now, no AD models have entirely validated the β-amyloid cascade hypothesis. AD models must be capable of recapitulating the critical events of this pathology, including β-amyloid plaques and neurofibrillary tangles. The development of plaques is probably derived from the amyloid precursor protein (APP) and presenilin 1 (PS1) familial Alzheimer’s disease (FAD) mutations, while the tangle-like pathology is determined by tau mutations. Transgenic mouse models struggle to replicate the entire spectrum of AD, particularly neuronal death stemming from β-amyloid and tau pathologies. Furthermore, the success of these transgenic mice often relies on the overexpression of APP transgenes enclosing FAD-associated mutations at levels beyond physiological. Ultimate species-specific discrepancies in genome and protein composition between the human and the mouse may hinder the accurate recapitulation of AD pathological events in mouse models. Although none of the AD models fully mirrors human pathology, these experimental in vivo animal models have provided valuable insights into β-amyloid toxicity and the overall pathophysiological basis of AD. Therefore, these experimental models have been widely used in the preclinical evaluation of therapeutic strategies and have played a pivotal role in the development of immunotherapies for AD. In this review, we sum up the main transgenic mouse models used for AD research, whether they are APP mutation-based mice, APP plus presenilin mutation-based mice, or tau mutation-based mice. The specific characteristics of each mouse model and the significance of their use for AD research, focusing on their current advantages and disadvantages, as well as on the progress made and the forthcoming challenges in replicating this neurodegenerative disease, are also highlighted.

1. Introduction

The World Health Organization (WHO) forecasts that by 2050 the number of people aged 60 and over will increase to 2.1 billion [1,2,3]. By definition, “ageing is the progressive accumulation of changes with time that are associated with or responsible for the ever-increasing susceptibility to disease and death” [4]. This process often leads to both cognitive and physical decline, which significantly raises the risk of developing dementia and other related neurodegenerative diseases [5,6]. The global prevalence of dementia, a syndrome characterised by brain dysfunction that impairs memory, behaviour, and daily functioning, has been escalating rapidly and is estimated to increase from 55 million in 2019 to 139 million by 2050 [1,7,8], alongside the huge cost associated with each patient.
Alzheimer’s disease (AD), the leading cause of dementia worldwide, is a neurological multifactorial and multigenetic disease characterised by a complex interplay of factors that lead to synaptic damage and neuron loss, predominantly affecting the cortex and the hippocampus [9,10]. This disorder is marked by the presence of β-amyloid plaques and neurofibrillary tangles in the brain, which are considered its primary pathological hallmarks [9,11,12]. β-amyloid plaques result from the accumulation of oligomers of the β-amyloid peptide, a consequence of abnormal processing of the amyloid precursor protein (APP) by α-, β-, and γ-secretases coupled with reduced degradation of β-amyloid. These plaques are toxic due to their innate misfolded structure, and consequently exposed chemical groups [10,12,13,14,15,16,17]. Neurofibrillary tangles, on the other hand, are hyperphosphorylated variants of the microtubule-associated tau protein, which aggregate due to the imbalance of phosphatase and protein kinase kinetic activities. These tangles disrupt the structure and function of neurons by accumulating in the cell body and dendrites of neurons [10,12,15,16,18].
The aggregates in the brain of AD include tau filaments and amyloid-beta (Aβ) filaments, both of which are essential for the pathological classification of AD. Understanding the nature of these aggregates is fundamental for distinguishing AD from other tauopathies and neurodegenerative conditions. Tau, a microtubule-associated protein, undergoes pathological modifications and misfolding in AD, leading to its assembly into amyloid filaments [19]. The tau filaments in AD exist as two structural types: (1) Paired helical filaments (PHFs) are twisted filaments with a periodicity of approximately 80 nm. They are the predominant form in AD and are closely associated with neurofibrillary tangles. (2) Straight filaments (SFs) are less common and lack the pronounced helical twist seen in PHFs. Both PHFs and SFs arise from the same core tau sequence but differ in their conformational arrangements. They accumulate in neurons, contributing to neurofibrillary tangles, a hallmark lesion of AD. However, tau aggregation alone is not sufficient to classify a condition as AD, as similar tau filaments are also found in other tauopathies like primary age-related tauopathy (PART), where Aβ filaments are absent [20].
Aβ, a peptide derived from the amyloid precursor protein (APP), forms extracellular amyloid plaques, another defining feature of AD. Aβ filaments are classified into two major structural types: (1) type I filaments, which are characterised by a specific fold seen predominantly in sporadic AD cases; (2) type II filaments, which have a distinct conformation and are often associated with familial AD and other rare forms of the disease [21]. Unlike tau, Aβ aggregation is exclusively extracellular and is thought to initiate upstream events in AD pathogenesis, including tau pathology and neuroinflammation [22]. Importantly, the simultaneous presence of tau filaments (PHFs and/or SFs) and Aβ filaments is required to diagnose AD, setting it apart from tau-only conditions like PART [23].
The coexistence of tau and Aβ filaments in the AD brain suggests a complex interplay between these proteins in disease progression. Aβ aggregation is hypothesised to trigger tau pathology through mechanisms involving synaptic dysfunction, oxidative stress, and inflammation. This dual aggregation forms a pathological feedback loop that accelerates neurodegeneration [24]. The simultaneous deposition is also a critical diagnostic marker that differentiates AD from other neurodegenerative conditions: PART involves tau aggregation in the absence of Aβ, typically occurring in aged individuals without cognitive impairment; other tauopathies, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), also lack Aβ filaments, further emphasising the uniqueness of AD pathology [25].
As AD has been recognised as a key public health issue in the last few decades, significant advances have been made towards AD understanding, but until now, no effective treatment exists to cure AD patients [8,26]. In this regard, research into AD, focusing essentially on understanding its underlying physiological processes as well as progressing on its premature detection and therapeutic strategies, remains a top priority.
The study of AD directly in humans is not considered ethical or practical, mostly due to the inaccessibility of the human brain and the limitations of post-mortem analyses, where many physiological systems are unfortunately no longer functional. To overcome this, several experimental disease models have been developed to gain clarity on the onset and progression of AD, as well as to advance novel potential diagnostic and therapeutic practices, including preclinical testing [16,27,28,29]. No existing experimental animal model has fully replicated the full spectrum of human AD, including pathological, biochemical, and behavioural characteristics. Despite significant advances in AD modelling, current experimental systems, including mouse models, fail to fully replicate the dual pathology of tau and Aβ filaments. Most models only partially mimic tau aggregation or Aβ deposition, but not their coexistence. This limitation hampers the ability to study the intricate molecular interactions underlying AD pathology and highlights the need for improved systems incorporating both hallmarks [30]. Since no animal naturally develops AD, one of the most viable and widely recognised models for the study of this disease is in vivo transgenic (Tg) animal models [27,28,31,32,33].
In vivo Tg animal models for AD research involve genetic modifications in the organism, in which specific genes associated with AD are introduced, deleted, or altered to create models that closely resemble the disease states in humans, reducing primate or human testing [34,35]. Tg models are extremely valuable not only for understanding the biological mechanisms of AD [16,27,33,35] but also for drug development and clinical assessment in preclinical testing since these models allow behavioural evaluation [16,24,27]. Mice are commonly used in these studies for several reasons: (1) being small mammals with genomes similar to humans, which allows for large-scale and cost-effective research [32,35,36]; (2) having a short lifespan, facilitating long-term studies on ageing and neurodegenerative diseases [16,36]; and (3) offering well-established protocols for genetic manipulation with numerous research reagents available, such as antibodies [37].
Since the late 1980s, over 200 mutations linked to AD have been identified, leading to the creation of several Tg mouse models that have significantly advanced our understanding of the disease [38]. Each model, depending on the mutation expressed, exhibits different pathophysiological and behavioural characteristics. The ongoing development of these models led to the creation of multi-transgenic models [38,39]. This review describes some, but not all, of the most established and well-characterised Tg mouse models created so far (Figure 1), emphasising the specific AD features they represent and discussing their advantages and limitations.

2. AD Transgenic Mouse Models

2.1. APP (Amyloid Precursor Protein) Mutation-Based Mouse Model

These Tg mouse models are built upon a key characteristic of AD, which is the accumulation of amyloid deposits in the extracellular spaces of the brain. Many of them are developed based on the transgenic overexpression of human APP, which is associated with distinct familial AD-associated mutations in the APP gene, leading to the production of distinct amyloid peptides that aggregate more promptly [40,41,42]. The overexpression of APP was the chosen methodology to replicate β-amyloidosis seen in the AD brain, leading to elevated β-amyloid levels; nevertheless, it also generates higher concentrations of APP fragments, like sAPP, CTF-α, CTF-β, and AICD, which can lead to unwanted side effects [40,41,42]. To address this issue, a novel generation of APP mutation-based mice (Knock-In mice) was developed. These mice show high β-amyloid levels without the overexpression of APP and its associated negative side effects [43,44]. Since the 1990s, various APP mutation-based models have been developed for AD research, each grounded on different mutations within the APP gene and distinct promoters, representing distinct components of the disease and different expression timelines, such as the PDAPP model, Tg2576 model, APP23 model, J20 model, TgCRND8 model, and AppNL-G-F Knock-In mouse model (Table 1).

2.2. APP and Presenilin Mutation-Based Mouse Model

Although APP-Tg mice conceal some of the most typical AD properties, they do not capture all aspects of the disease. To achieve this, researchers have combined the aforementioned AD models with other familial AD-associated mutations to achieve a model encompassing the missing AD pathological features. Presenilin genes (PS-1 and PS-2) are known to harbour various familial AD-related mutations and encode for proteins that are vital constituents of the γ-secretase complex, which are intricated on the cleavage of APP, among other cellular roles [40,41,42,45]. Mutations in these genes often lead to altered secretase cleavage, resulting in increased production of amyloidogenic β-amyloid, thus promoting β-amyloid deposition, neuronal loss, and cognitive decline [42,45]. Since the late 1990s and early 2000s, numerous models combining APP and PS mutations have been developed for AD research, including Knock-In mice. These models rely on distinct mixtures of mutations in the APP and PS genes and different promoters and exhibit distinct timelines of disease onset. These transgenic mice are divided into the following specific research models: APP/PS1 (Tg2576 x PS1), APP/PS1 (APPswe/PSEN1ΔE9), APPSL/PS1, PS2APP, APPSLPS1 Knock-In, and 5xFAD (Table 1).

2.3. Tau Mutation-Based Mouse Model

Mouse models based on APP and APP/PS mutations account for various relevant pathological features of AD. Nevertheless, the characteristic neurofibrillary tangles, associated with tau pathology, are still missing. To address this, researchers have developed mice with mutations in the MAPT (microtubule-associated protein tau) gene, which encodes tau protein, most of the time combining these with previously used mutations. This approach aims to create a mouse model that fully replicates AD pathological disorder. Tau is a microtubule-related protein essential for stabilising the neuronal cytoskeleton through its role in microtubule dynamics [18,46]. These mutations in the MAPT gene can either change the tau protein’s amino acid sequence, leading to hyperphosphorylation, diminished microtubule assembly, and intensified aggregation, or cause disturbances in the isoforms of tau’s protein because of abnormal splicing, which also results in both hyperphosphorylation and aggregation [18,46,47,48]. From the early 2000s on, various MAPT mutation-based mice, including Knock-In mice, have been developed for AD study. These models feature several mutations in the MAPT gene, using different promoters, and often combine these with both APP gene or PS gene mutations, each representing distinct aspects of AD and varying in disease manifestation timing. These transgenic mice are divided into the following specific research models: JNPL3, PS19, rTg4510, TAPP, 3xTg, and APPNL-G-F/Mapt Knock-In (Table 1).
Table 1. Overview description of APP, APP, presenilins, and Tau mutation-based mouse models.
Table 1. Overview description of APP, APP, presenilins, and Tau mutation-based mouse models.
β-Amyloid Aggregates
(Appearance)		Neurofibrillary Tangles
(Appearance)		NeuroinflammationNeuron LossBehavioural Disturbances
(Appearance)		Refs.
APP Mouse Models
PDAPPYes
(6–9 months)		NoYesNoYes
(3 months)		[49,50]
Tg2576Yes
(11–13 months)		NoYes YesYes
(9 months)		[51,52]
APP23Yes
(6 months)		NoYesYesYes
(3 months)		[53,54,55,56]
J20Yes
(7–9 months)		NoYesYesYes
(4 months)		[57,58,59]
TgCRND8Yes
(3 months)		NoYesNoYes
(3 months)		[60,61,62,63]
APPNL-G-F Knock-InYes
(2 months)		NoYesNoYes
(6–9 months)		[43,64,65,66,67]
APP + PS Mouse Models
APP/PS1 (Tg2576 x PS1)Yes
(6 months)		NoYesNoYes
(3–6 months)		[68,69,70,71]
APP/PS1 (APPswe/PSEN1ΔE9)Yes
(4 months)		NoYesYesYes
(8 months)		[72,73,74,75,76,77,78,79,80]
APPSL/PS1Yes
(2.5 months)		NoYesYesYes
(9 months)		[81,82,83,84,85,86]
PS2APPYes
(5–6 months)		NoYesNoYes
(7–8 months)		[87,88,89,90]
APPSLPS1
Knock-In		Yes
(2–3 months)		NoYesYesYes
(6 months)		[91,92,93,94,95]
5xFADYes
(2 months)		NoYesYesYes
(1–4 months)		[96,97,98,99,100,101,102,103,104]
Tau Mouse Models
JNPL3NoYes
(4.5 months)		YesYesYes
(7–10 months)		[105,106,107]
PS19NoYes
(5–6 months)		YesYesYes
(3–8 months)		[108,109,110,111]
rTg4510NoYes
(4 months)		YesYesYes
(2.5–4 months)		[112,113,114,115,116]
TAPPYes
(6 months)		Yes
(3 months)		YesYesYes
(7–10 months)		[117,118,119,120]
3xTgYes
(6 months)		Yes
(12 months)		YesYesYes
(6 months)		[121,122,123,124,125]
APPNL-G-F/Mapt Knock-InYes
(6 months)		NoYesYesYes
(9 months)		[126,127,128,129]

2.4. Another Mutation-Based Mouse Model for Exploring Amyloid-Driven Neurodegeneration

The transgenic mouse models ARTE10, Tg-SwDI, and TgAPPswe each target distinct aspects of AD pathology. ARTE10 mice, carrying Swedish and Arctic APP mutations, exhibit rapid Aβ oligomer accumulation and cognitive decline. Tg-SwDI mice, with Swedish, Dutch, and Iowa mutations, develop severe cerebrovascular amyloidosis, making them ideal for studying vascular amyloid pathology. TgAPPswe mice, expressing the Swedish mutation, show early amyloid plaques in the hippocampus and the cortex regions, being therefore useful for investigating synaptic dysfunction. These transgenic mouse models provide complementary tools for exploring amyloid-driven neurodegeneration [130,131,132].

3. Comparisons on Pathogenic Aspects Between AD in Mouse Models and Humans

The comparison between AD pathology in murine models and humans is essential for advancing our understanding of the disease and improving the development of treatments. First, murine models allow researchers to investigate AD’s progression under controlled conditions, enabling studies on how amyloid plaques, tau tangles, and other pathological features develop over time. These models are invaluable in testing hypotheses about AD mechanisms and identifying therapeutic targets, as they allow precise genetic modifications, like APP and tau mutations, that trigger certain AD-like features, which would not be ethical or feasible in human studies [42].
However, these models often fail to capture the full complexity of human AD, especially in aspects like synaptic loss, neuroinflammation, and cognitive decline, which progress more gradually in humans and are influenced by diverse genetic and environmental factors. This discrepancy underscores the importance of carefully comparing findings between species to determine which model findings are likely applicable to human AD and which aspects may need alternative models or additional validation. Additionally, differences in biomarkers between mice and humans highlight the need for biomarker research to confirm that observed changes in model studies reflect real human disease processes, especially for clinical trials that rely on biomarkers to evaluate treatment efficacy [28,133].
A comparison of AD pathology in mouse models and humans is detailed in Table 2.
The abovementioned comparison reveals both critical similarities and limitations. Amyloid plaques are a central feature of AD, and although murine models commonly produce these plaques through genetic modifications, their distribution and onset differ from the gradual accumulation seen in humans. Tau-based neurofibrillary tangles, another hallmark of human AD, are rare in murine models unless specific human tau mutations are introduced; even then, the tangles are less extensive and lack the progressive nature observed in human patients. Synaptic loss and cognitive impairment, key contributors to AD-related memory and functional decline in humans, are also present in some murine models, though they are generally less severe. Neuroinflammatory responses and oxidative stress, prominent in human AD, are replicated in murine models but tend to be less intense and localised, limiting the models’ effectiveness in fully simulating AD’s chronic neurodegeneration. Similarly, mitochondrial dysfunction and cholinergic system degradation, crucial aspects of human AD pathology, appear in some mouse strains but with milder effects. AD’s progression in humans is slow and complex, often spanning decades, while murine models exhibit a much faster onset and progression due to their genetic modifications. Finally, the overlap in biomarkers, such as Aβ42 and tau, is limited, and biomarkers like neurogranin do not translate directly, impacting the applicability of murine models for biomarker-based research. These differences emphasise the value of murine models for studying specific AD features but highlight the need for complementary approaches to capture the full scope of human AD pathology.

Correlation of the AD Condition Between Humans and Mouse Models

Mouse models play a critical role in studying AD, particularly due to the deposition of Aβ and tau aggregates. However, they fail to fully replicate the structural features observed in the human AD brain. Concerning Aβ in mouse models, transgenic mouse models, such as APP/PS1 and 5xFAD, produce Aβ plaques that partially mimic human structures. While their cross-beta sheet architecture resembles human Aβ filaments, the specific folds (type I and II) observed in AD brains are not replicated. Humanised APP Knock-In models and cross-seeding with human Aβ filaments improve structural mimicry but do not fully recapitulate human-like stability or ultrastructure due to differences in Aβ proteostasis and processing enzymes [152]. Concerning tau aggregates in mouse models, human AD is characterised by paired helical filaments (PHFs) and straight filaments (SFs) of tau, which mouse models fail to reproduce due to sequence differences and limited post-translational modifications. The humanised tau models, like P301S, produce neurofibrillary tangles but lack the complexity of human tau filaments. Cross-seeding with patient-derived tau enhances replication but still deviates from native human structures [153].
Aggregation-prone mutations are often used in experimental mouse models, but such mutations are absent from AD patients. Additionally, the presence of these mutations is most likely obstructing the assembly of tau into PHFs and SFs due to the nature of the new amino acids and the incompatibility with the final atomic structure [154]. However, there are reported atomic structures for some mouse models, namely PS19 [108,109,110,111] and tg4510 [112,113,114,115,116]. All of them are remarkably different from the PHFs and the SFs observed in AD [154].
Species-specific factors, such as differences in lipid composition, inflammatory responses, and post-translational modifications, influence aggregate formation in mouse models. These factors create discrepancies in Aβ and tau aggregation, limiting the models’ relevance to human AD pathology [155]. Advances in humanised models and patient-derived seeding techniques hold promise for bridging these gaps.

4. Benefits and Limitations of the Use of AD Transgenic Mouse Models

Among vertebrates, mice are the most used laboratory animal models for AD research. As described in this review, transgenic mice reflect a broad spectrum of AD features, permitting extended research and therapeutic assessment of Aβ pathology [16]. This preference is due to various reasons, starting with the low-cost and well-established use of transgenic technology in mice. Additionally, mice have a short lifespan, are small with low nutritional cost, and are easily handled and maintained in laboratory settings with regulated environmental conditions, like temperature (20–24 °C), lighting (14 h light/10 h dark), ventilation (15 changes/hour), and humidity (50–60%) [156]. Moreover, mice exhibit a well-characterised behavioural phenotype [27].
Conversely, Tg mice face numerous challenges, including the major struggle in recreating the full range of AD pathology. These mice display a considerable variation in AD phenotypes across research models and some discrepancies when compared to the human AD brain [16].
Regarding behaviour analysis, it is currently uncertain whether plaque appearance and cognitive impairment in mice fully resemble those occurring in human AD. Many of these mouse models show behavioural deficits before the onset of drastic β-amyloid deposition [157], whereas considerable plaque deposition often precedes cognitive symptoms in AD subjects [158].

5. Concluding Remarks and Forthcoming Directions

Research reports using Tg mice for AD research are convincing enough for defining novel drug targets and designing new therapeutic approaches. So far, only seven drugs for AD treatment have been approved by the American Food and Drug Administration (FDA), of which five solely focus on alleviating the symptoms of the disease [159]. Recently, additional medication, such as anti-amyloid β (anti-Aβ) monoclonal antibodies (mAbs), aimed at slowing disease progression have been developed and approved by the FDA, despite having several adverse effects [160]. This limited number of approved treatments highlights the ongoing challenges in AD research and underscores the significant gaps in our understanding of AD pathogenesis and development.
To enhance our understanding of AD, transcriptomic and proteomic methods have facilitated the discovery of new distinctively regulated genes and their corresponding proteins [28]. These techniques are being applied in animal models for AD, despite the associated high costs. Omics approaches can provide a more comprehensive assessment of disease pathogenesis by enabling genome- or proteome-wide screening to identify modified networks across this pathology. So far, proteomics research in Tg mice suggests mitochondria as the initial target for Aβ and tau aggregation [161]. Moreover, advances in neuroimaging assessment are expected to deliver vital knowledge into the disease development in AD patients [28]. By employing state-of-the-art imaging technology in both AD patients and mouse models, early preclinical AD diagnosis could become achievable [146].
In addition to ethics and legal constraints [16], significant limitations have arisen regarding the use of experimental animal models in translational medicine [162]. These limitations include the following: (1) a notable discrepancy between preclinical animal models and AD patients in clinical trials; (2) unlike inbred mouse strains, the clinical trial participants often exhibit considerable heterogeneity; and (3) most models used focus on familial AD, while the majority of cases in the population are indeed sporadic AD. The last AD is the most prevalent form of AD and lacks a distinct familial link, deriving from an intricated interplay of genetic, environmental, and lifestyle factors, with ageing being the primary risk factor.
Given that the incidence of AD is expected to triple in the next decades, there is an urgent need for preventive measures and effective therapeutic options. Future efforts should focus on increasing the participation of AD patients in clinical assays and deeply engaging research on the pursuit of novel predictive biological markers, which will also enlighten genetic odds and lifestyle risk factors. By directing AD research towards the AD patient, the chances of discovering new methodological strategies and drug targets to prevent, mitigate, and potentially reverse this neurodegenerative disease may improve. The clock is ticking…

Author Contributions

Conceptualisation, J.L.G.-G.; writing—original draft preparation, M.S.P., P.A.L. and J.L.G.-G.; writing—review and editing, J.L.G.-G. and P.A.L.; visualisation, J.L.G.-G.; supervision, J.L.G.-G. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by Fundação para a Ciência e a Tecnologia (FCT, Lisbon, Portugal) through the UIDB/00276/2020 project to CIISA, the LA/P/0059/2020 project to AL4AnimalS, and the FCT.2022.08133.PTDC project (DOI: 10.54499/2022.08133.PTDC). This study was also financially supported by national funds through the FCT Stimulus of Scientific Employment Program to P.A.L. (DOI: 10.54499/DL57/2016/CP1438/CT0007).

Conflicts of Interest

The authors declare no conflicts of interest.

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Jdad 02 00002 g001
Figure 1. Tg mouse models for AD research.
Figure 1. Tg mouse models for AD research.
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Table 2. Comparisons of pathogenic aspects between AD in mouse models and humans.
Table 2. Comparisons of pathogenic aspects between AD in mouse models and humans.
Pathogenic FeatureAD in Murine ModelsAD in HumansReferences
Amyloid plaquesCommonly produced in transgenic models (e.g., APP and PSEN1 mutations) and often with faster onset and artificial induction. Distribution and plaque composition differ from humans.Characterised by Aβ plaques, primarily Aβ42, with widespread distribution in cortical and hippocampal regions. Plaque deposition is linked to neuronal death.[134,135]
Fibrillary tanglesRarely seen in murine models unless human tau mutations are introduced (e.g., P301L and P301S), but typically, tangles are less extensive and not progressive.Hallmark of AD, with abundant tau tangles in the brain, progressing from the transentorhinal cortex to the hippocampus, ultimately affecting most cortical areas.[122,136]
Synaptic loss and dysfunctionReduced synaptic density is observed in specific regions; some models (e.g., 5xFAD) better replicate synaptic dysfunction, though it is typically milder than in humans.Progressive synaptic degeneration leads to significant cognitive deficits involving severe loss in hippocampal and cortical synaptic networks.[137,138]
Cognitive impairmentDetected through memory and navigation tasks (e.g., Morris water maze); impairment is typically present but less severe than in human AD.Profound memory loss, language impairment, and executive dysfunction, affecting daily activities; progressive and irreversible cognitive decline.[139,140]
NeuroinflammationMicroglial activation occurs and is often less extensive than in humans; the inflammatory response differs in scale and type, with milder glial activation.Chronic neuroinflammation with substantial microglial and astrocytic activation leads to ongoing neuronal damage and contributes to AD pathology.[141,142]
Oxidative stressObserved in some models (e.g., APP/PS1) but often limited to specific brain regions; levels are generally lower than those observed in human AD.High oxidative stress, particularly in the hippocampus and cortex, contributes to cell damage and death and involves lipid peroxidation, protein, and DNA damage.[143,144]
Mitochondrial dysfunctionSome models display early mitochondrial dysfunction, though it is generally less severe; defects in energy metabolism are present but vary by strain.Extensive mitochondrial dysfunction, impacting energy metabolism and increasing reactive oxygen species, with notable impairments in neurons, especially in the hippocampus.[145,146]
Cholinergic system dysfunctionSome cholinergic deficits are observed, but models rarely fully replicate the widespread cholinergic loss seen in human AD.Significant degeneration of the basal forebrain cholinergic system, correlating with memory loss and cognitive decline in AD patients.[147,148]
Disease onset and progressionOnset is generally rapid due to genetic modifications, and progression is accelerated compared to humans; models capture acute aspects of pathology.Gradual and complex onset, often spanning decades; progression is slow, with a prolonged preclinical phase, progressing to clinical and severe dementia stages.[135,140]
Genetic influenceGenetic modifications (e.g., APP, PSEN1, PSEN2, and tau mutations) are essential for disease induction in models but lack the full diversity of human AD genetics.Genetic factors (e.g., APOE4 allele) influence AD risk, but the disease is also affected by complex, non-genetic factors, including lifestyle and environmental elements.[149,150]
BiomarkersLimited biomarkers overlap; Aβ42 and tau are often measured, but other AD biomarkers (e.g., neurogranin) may not correspond directly to those in humans.Biomarkers include Aβ42, tau, phospho-tau, and neurofilament light chain, which aid in diagnosis and monitoring of disease progression.[28,42,151]
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Lopes, P.A.; Pádua, M.S.; Guil-Guerrero, J.L. An Overview of Transgenic Mouse Models for the Study of Alzheimer’s Disease. J. Dement. Alzheimer's Dis. 2025, 2, 2. https://doi.org/10.3390/jdad2010002

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Lopes PA, Pádua MS, Guil-Guerrero JL. An Overview of Transgenic Mouse Models for the Study of Alzheimer’s Disease. Journal of Dementia and Alzheimer's Disease. 2025; 2(1):2. https://doi.org/10.3390/jdad2010002

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Lopes, Paula Alexandra, Mafalda Soares Pádua, and José L. Guil-Guerrero. 2025. "An Overview of Transgenic Mouse Models for the Study of Alzheimer’s Disease" Journal of Dementia and Alzheimer's Disease 2, no. 1: 2. https://doi.org/10.3390/jdad2010002

APA Style

Lopes, P. A., Pádua, M. S., & Guil-Guerrero, J. L. (2025). An Overview of Transgenic Mouse Models for the Study of Alzheimer’s Disease. Journal of Dementia and Alzheimer's Disease, 2(1), 2. https://doi.org/10.3390/jdad2010002

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