Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic lateral sclerosis (ALS), involve the progressive degeneration of structure or function, and death of neurons. The diseases have several common pathological and pathogenetic characteristics, such as specific protein aggregation, mitochondrial dysfunction, neuro-inflammation, and iron toxicity. Also, oxidative and nitrosative stresses are affected in the pathology of neurodegenerative disease [
31,
32]. However, the critical pathogenesis and therapeutics of neurodegenerative disease remains mostly unknown. Recently, many researchers have focused on diet therapy of neurodegenerative diseases for treatment. The neuroprotective effects of some polyphenol dietaries can be potentially useful for treatment or pharmacotherapy as suggested by several studies (
Table 2). This review also discusses the potential therapeutic applications of polyphenols in neurodegenerative diseases using the
Drosophila model.
3.1. Alzheimer’s Disease (AD)
Alzheimer’s disease (AD) is a prevalent and progressive chronic neurodegenerative disease. Decreasing verbal ability and motor neuron function and cognitive impairment are symptoms of AD. On average, AD patients live for 8 years post-diagnosis, depending on individual age and other health conditions [
48,
49]. This disease is related to a brain pathology that includes neurofibrillary tangles composed of hyperphosphorylated Tau protein and senile plaque formation composed of amyloid beta protein (Aβ) aggregates [
50]. Tau plays an important role in modeling microtubules and bridging these polymers with other cytoskeletal filaments [
51]. Since the tau protein becomes tangled in nerve cells, microtubules break up and destroy cellular structure. These events induce disintegration of the transportation system and miscommunication between neurons, and finally lead to cell death. Extracellular aggregates of amyloid plaques mostly consist of abnormally folded products of both amyloid precursor protein (APP) metabolism, Aβ40, and Aβ42 [
52]. In the brain of AD patients, Aβ42 is highly amyloidogenic and accumulates more commonly than Aβ40 [
48,
52]. The number of AD patients is growing rapidly, and there are no effective treatments yet. That is why new drugs for AD treatment and prevention are needed. The use of plant-derived extracts and ingredients for the treatment and prevention of many types of diseases, including AD, is widely reported.
Among various plant-derived extracts or products for curing AD, grape-seed polyphenolic extract (GSPE) was used to prevent the abnormal oligomerization of Aβ in a mouse model of amyloid neuropathology [
53,
54], and to break down existing aggregated tau peptides in vitro [
55]. Moreover, GSPE has a beneficial role in tau-mediated neuropathology in
Drosophila models. Overexpressing
R406W mutant tau in the fly eye results in a dramatic reduction and degeneration of the eye morphology. Among these phenotypes,
R406W mutant tau is one of the modeled aspects of tauopathy in the
Drosophila model [
56]. GSPE therapy in flies overexpressing mutant tau in the eye results in the recovery of eye size and morphology. GSPE-mediated ameliorations in the
Drosophila eye model likely take place following the manufacture of the toxic protein, but upstream of caspase activation [
33].
Additionally, polyphenols in adzuki beans are known to inhibit the aggregation of various amyloid proteins [
57,
58]. Deposition of Aβ42 aggregates in the brain and oxidative stress are AD symptoms. Adzuki bean extract restored the memory abnormalities in Aβ42 overexpressing flies, originally caused by the suppression of Aβ42 aggregation and oxidative stress. Also, defects in mobility and the shortened lifespan of the fly model were restored by the adzuki bean extracts [
34]. Thus, adzuki bean polyphenols may delay the progression and prevention of AD.
Since
Arabidopsis thaliana grows rapidly, and has been fully sequenced, its extracts are widely used in research. These extracts might also be applicable in AD therapy, as they are rich in phenolic compounds useful against inflammation by activating the Nrf2 pathway in BV2 cells.
Drosophila overexpressing the human Aβ42 peptide were used to confirm the activity of phenolic compounds in
Arabidopsis thaliana. Supplementation of polyphenolic extracts restored the defective climbing ability of AD-induced flies [
35].
Tobacco and coffee, containing nicotine or caffeine, provide the symptomatic alleviation that may lead to neuroprotection [
59,
60]. The neuroprotective impacts of coffee and tobacco were not derived from caffeine or nicotine in a PD model [
36,
59,
61]. Decaffeinated coffee and nicotine-free tobacco restored defective phenotypes, including damaged climbing ability, reduced survival rate and declined eclosion rate in an AD fly model induced by Aβ42 overexpressed [
36]. These studies suggest that decaffeinated coffee and nicotine-free tobacco confer significantly protective effects on the AD model.
3.2. Parkinson’s Disease (PD)
Parkinson’s disease (PD) is the second most common neurodegenerative disease after AD, and is characterized by progressive and selective loss of dopaminergic neurons from the substantia nigra region of the brain [
62]. PD is grouped as sporadic or familial and is specific when the specific cause is unknown, but related to oxidative stress [
63]. Genetic mutations in specific proteins, including PARK2 (parkin), SNCA (α-synuclein), PINK1 (pink1), and PARK7 (DJ-1), leads to familial PD [
64,
65,
66]. One of the pathological hallmarks of PD is the formation of Lewy bodies, including the abnormal expression of α-synuclein, a presynaptic neuronal protein related to regulation of the dopamine and a major fibrillar component of Lewy bodies [
67]. Under pathological conditions, α-synuclein becomes insoluble and forms toxic accumulations [
68]. The exact cause of PD still remains poorly understood but oxidative stress plays an important role in neuronal decline [
69]. Further, exposure to environmental toxins like MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and paraquat (PQ) induce severe and irreversible parkinsonism [
70,
71,
72]. Since, PQ
2+ has a similar chemical structure to MPP
+, which is an active metabolite of MPTP, it is presently used in PD models [
73]. Traditional herbal compounds with antioxidant properties are a proven source for therapeutic drug development for PD [
74].
For example, the root extract of
Decalepis hamiltonii (
Dh) is known as a novel natural antioxidant. Dietary supplementation with
Dh root extract antioxidants in flies overexpressing both missense mutations (A30P and A53T) of α-synuclein restored defective motility and circadian rhythm, as well as diminution of ROS and lipid peroxidation, and enhancement of catalase and SOD activities. Indeed,
Dh extract reduced neurotoxicity against PQ sensitivity due to the mutations [
37] and it can be used in PD therapy to defer the onset of PD.
Similarly to
Dh, avocado
(Persea americana), a fruit broadly cultivated in tropical and subtropical climates globally [
75], is also a source of antioxidants for PD treatment. The Colinred peel (CRE) and epicatechin (EC) in methanolic
P. Americana extracts protect
parkin knockdown flies exposed to PQ by enhancing the lifespan and locomotor activity. Hence, its extract can protect
parkin knockdown flies against PQ-induced oxidative stress, mobility damage, and lipid peroxidation [
38].
Among the polyphenols from fruits, tangeritin, a flavonoid, found in the peels of Mandarin oranges, has various biological activities, such as neuroprotection, improving the gap junction intercellular communication, apoptosis, and antimetastasis [
76,
77,
78,
79]. The exposure of PD flies to tangeritin increased the dopamine content and restored the reduction in locomotive activity and various oxidative stress markers, such as lipid peroxidation, reduced glutathione, glutathione
s-transferase, protein carbonyl content, and monoamine oxidase activity [
39]. Therefore, supplementation of tangeritin led to a reduction in PD symptoms, suggesting its potential application in dietary therapy.
Grape and grape seed extracts, rich in polyphenols (flavonoids and GA), are well-known sources of antioxidants in neurodegenerative disease therapy [
33,
40,
45]. When the extract was fed to flies expressing α-synuclein, female flies showed significantly expanded longevity and male flies showed highly enhanced climbing ability, confirming the ability of grape extracts to protect against free radicals and free radical-induced lipid peroxidation and DNA damages [
40].
Treatment with capsaicin exerted a protective effect on PD flies induced with overexpressed α-synuclein, leading to delayed reduction in climbing ability. Supplementation with capsaicin is a potential agent for delaying PD development [
41]
Due to its biological functions, such as antioxidation, anti-inflammation, and prevention of several diseases, tea drinking is popular worldwide. Black tea has a protective effect against PD symptoms in PD-induced flies using a model exposed to
l-dopamine, by delaying the reduction in lipid peroxidation and protein carbonyl content, increasing glutathione and dopamine content, and reducing glutathione
s-transferase activity in a dose-dependent manner [
42].
As already mentioned, decaffeinated coffee and nicotine-free tobacco had neuroprotective effects in an AD fly model in a similar manner to that in the PD transgenic fly overexpressing the α-synuclein and loss-of-function
parkin gene mutant. Decaffeinated coffee and nicotine-free tobacco have neuroprotective effects through the activation of the cytoprotective transcription factor Nrf2 [
36]. Hence, these compounds serve as therapeutic candidates in AD and PD models.
Polyphenolic extracts, phenolic acids, and flavanols, have antioxidant activity and protective effects against PD-induced exposure to iron and PQ. Pure polyphenols, including GA, caffeic acid (CA), propyl gallate (PG), and epigallocatechin-3-gallate (EGCG), rescued the impaired climbing capability induced by PQ in the fly. PG and EGCG polyphenols in particular protected the locomotive capability of flies cotreated with PQ and iron [
80]. Besides, curcumin exposure in α-synuclein overexpressing PD flies dramatically increased the life span and reduce oxidative stress, representing a reduction in lipid peroxidation and protein carbonyl content, and apoptosis [
43]. GA significantly preserved the number of dopaminergic neurons, and improved life span and locomotive activities under PQ treatment [
44]. Therefore, the various polyphenolic compounds discussed are potential sources for drug therapy of neurodegenerative disease.
3.3. Huntington’s Disease (HD)
Huntington’s disease is an autosomal neurodegenerative disease characterized by the degeneration of neurons and cognitive symptoms, which finally results in death. HD is caused by the elongation of a polymorphic CAG triplet repeat in the first exon of the
huntingtin (
HTT) gene that is translated to an elongated polyglutamine (polyQ) repeat in the mutant huntingtin (htt) protein [
81,
82]. Mutant htt aggregate formation by its N-terminal cleavage is implicated in HD toxicity, which leads to neuronal damage and loss [
83]. The inclusion of mutant htt negatively affects intracellular processes acting as mitochondrial and transcriptional systems of genes, disturbed calcium signaling, aberrant protein–protein interactions, adjustments in the ubiquitin-proteasomal system, and autophagy [
81]. Therefore, the inhibition of abnormal htt protein aggregate formation is a novel approach for HD therapy.
One of the dietary control treatments for HD is GSPE, like in AD [
45]. Postmortem brains of HD patients showed increased oxidative damage [
84,
85], thus oxidative stress is a representative indicator of HD pathogenesis. GSPE could physically disrupt the aggregation of Aβ and Tau peptides [
33,
53,
55]. Moreover, GSPE treatment dramatically prolonged lifespan in
Drosophila and R6/2 mouse HD models and also rescued the motor defects in the mice [
45].
Another HD treatment is green tea. Among the green tea polyphenols, EGCG blocks the mutant htt protein aggregates in a dose-dependent manner. In a yeast HD model, EGCG treatment dramatically down-regulated polyQ-mediated htt protein aggregation and cytotoxicity. Photoreceptor degradation and motor deficits were restored in transgenic HD flies overexpressing the pathogenic htt when fed with EGCG [
46]. Although treatment with green tea did not change the reduced viability induced by mutant huntingtin, supplementation with green tea infusion mitigated the reduced lifespan and neurodegeneration caused by the mutant huntingtin in a
Drosophila model [
47]. Therefore, green tea consumption could become a reasonable HD therapy.