Stem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer’s Disease

Table 3

Physiological factors involved in AD.

S. No	Factors	Effect in AD	References
1.	Apoptosis	(i) Studies have shown extracellular and intracellular Aβ mediated activation of caspases either through the extrinsic or the intrinsic pathway.	[192, 193]
		(ii) Aβ binding to alcohol dehydrogenase can activate mitochondrial stress mediated apoptosis.	[194]
		(iii) Caspases and Calpains are proteases responsible for Tau proteolysis, and their activation has been found to play a role in apoptosis.	[195, 196]
		(iv) The lysosomal protease Cathepsin D expressed in the brain regulates apoptosis, thus contributing to AD.	[197]
		(v) P2X7, a purinoreceptor involved in AD pathogenesis promotes cell death by apoptosis.	[198]
		(vi) Altered expression of caspase-3, Bax, p53, Bcl-2 and Par-4 apoptotic proteins occurs in AD.	[199]
		(vii) TRAIL binding to death receptor 5 (DR5) has been shown to initiate Caspase-8 mediated apoptosis in AD neurons.	[200]
		(viii) Aβ-induced synthesis of disialoganglioside GD3 is involved in apoptosis induction in cortical neurons.	[201]
		(ix) In neurons, over-expression of initiates Aβ mediated apoptosis through activation of caspase-9 and caspase-3. An additional copy of RCAN1 on chromosome 21 promotes AD pathogenesis.	[199]
		(x) Regulation of AICD mediated neuronal apoptosis occurs via GSK3β and p53.	[202, 203]
		(xi) PSEN1 mutants exhibit increased Aβ generation, altered calcium homeostasis and an augmented sensitivity to ER stress-induced apoptosis.	[204]
		(xii) Increased caspase-4 in AD brains relates to ER stress-induced apoptosis.	[205]
2.	Autophagy	(i) Increased levels of lysosomal protease occur in AD patients.	[206]
		(ii) In Drosophila melanogaster, age-related down-regulation of expression of atg1, atg8a and atg18 was associated with late onset of AD.	[207]
		(iii) In ATG7 knockdown mice, significant reduction in Aβ secretion was followed by intracellular Aβ accumulation.	[208]
		(iv) The RAGE-calcium-CaMKKβ-AMPK pathway was found to regulate the Aβ-induced formation of autophagic vacuoles.	[209]
		(v) Tau hyperphosphorylation is implicated in autophagy dysfunction.	[210, 211]
		(vi) Tau degradation has been found to be regulated by Nrf2-mediated activation of NDP52 autophagy receptor.	[212]
		(vii) Beclin-1 deficiency resulted in an elevation of APP, Aβ and the C-terminal fragment (CTF), while its over-expression caused a reduction in Aβ accumulation.	[213–215]
		(viii) Rapamycin has been shown to reduce Aβ and Tau pathology and improve cognition.	[216, 217]
3.	Oxidative Stress	(i) A decrease in reduced glutathione (GSH) causes excess ROS production leading to oxidative stress, thus favoring AD pathogenesis.	[218]
		(ii) Aβ induces lipid peroxidation and its products.	[219]
		(iii) Breakdown products of oxidative stress, such as malondialdehyde, acrolein, F2-isoprostanes and 4-hydroxy-2,3-nonenal (HNE), are observed in AD brains.	[220–223]
		(iv) Localization of increased levels of 8OHdG and 8OHD (associated with DNA and RNA oxidation) in Aβ plaques and NFTs is shown.	[224–227]
		(v) In AD, accumulation of extracellular advanced glycation end products (AGEs) occurs due to increased oxidation of glycated proteins.	[228]
4.	Mitochondrial Dysfunction	(i) A significant increase in mtDNA and cytochrome oxidase (COX) in AD neurons is reported.	[229–231]
		(ii) Association of mitochondrial pathology in AD with loss of dendritic branches, dystrophic dendrites and abnormal alteration of the dendritic spines is evident.	[232, 233]
		(iii) C57B6/SJL Tg AD mice showed increased levels of mtDNA deletion, amyloid deposition, mitochondrial structural abnormalities and oxidative stress markers.	[234, 235]
		(iv) In AD, accumulation of AβPP across mitochondrial import channels restricts entry of COX subunits IV and Vb leading to a decrease in COX activity and elevated H2O2 levels.	[236]
		(v) In the triple Tg AD mouse model, increased levels of lipid peroxidation, GPx, and SOD, but decreased levels of vitamin E and GSH, were observed.	[237]
		(vi) A γ-secretase complex, composed by PEN2, APH-1, and NCT, was identified in the rat brain mitochondria and was shown to cleave AβPP into Aβ and AβPP intracellular domain.	[238]
		(vii) In AD, a decrease in dynamin-like protein 1 (DLP1) and OPA1 and increase in Fis1 levels, thereby leading to mitochondrial abnormalities, have been reported.	[239, 240]
		(viii) Studies show that Aβ peptides in the presence of Ca^2+ aggravate opening of mitochondrial PTP.	[241, 242]
		(ix) In PC12 cells exposed to Aβ40 and Aβ25–35, inhibition of complexes I, III, and IV of the mitochondrial respiratory chain was observed, thereby leading to mitochondrial dysfunction.	[243]
5.	Inflammation	(i) Associations between AD pathogenesis and mutations in TREM2, CD33 have been established.	[127, 244, 245]
		(ii) Aβ binding to CD36 or TLR4 leads to the production of inflammatory cytokines.	[246, 247]
		(iii) In AD animal models, elevated levels of pro-inflammatory markers IL-1, IL-6, GM-CSF, IL-23, IL-12, and TNF were detected.	[248–251]
		(iv) Microglia from Tg AD mice has shown reduced Aβ-binding scavenger receptor and Aβ-degrading enzyme levels.	[252]
		(v) Anti-inflammatory factors in neurons such as CD200, CD59, and fractalkine have been shown to be down-regulated in AD brains.	[253–256]
		(vi) In the human AD brain, endothelial cells have been shown to produce IL-1β, CCL2, and IL-6 immune molecules.	[257]