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

Table 1

Genetic factors involved in AD.

S. No.	Genetic Factors/Mutations	Effect in AD	References
1.	R47H (Variant of TREM2)	It compromises microglial mediated clearance of aggregation-prone proteins in AD	[113]
2.	KIAA1462	It increases the risk of coronary artery disease, resulting in compromised blood flow to the brain, and increases oxidative stress and inflammation	[114]
3.	APOE ε4	ApoE regulates lipid homeostasis. ε4 allele increases the risk of AD by initiating and accelerating Aβ accumulation, aggregation, and deposition in the brain	[12]
4.	P21	P21 (cyclin-dependent kinase inhibitor) levels significantly decreased in peripheral blood lymphocytes of AD patients	[115]
5.	SORL1	SORL1 gene encodes a protein LR11 responsible for cargo transport, chaperone-like activity, signaling, and intracellular sorting. Down-regulation or dysfunction of LR11 has been shown to lead to amyloidogenesis.	[116]
6.	PSEN1	Presenilin-1 functions as the catalytic subunit of γ-secretase that cleaves APP. PSEN1 mutations initiate disease pathogenesis by increasing production of Aβ42.	[117]
7.	PSEN2	Presenilin-2 is the main component of the γ-secretase complex along with PSEN1. PSEN2 mutation alters the γ-secretase activity and increases Aβ 42/40 ratio.	[118, 119]
8.	CLU	The clusterin gene acts as an extracellular chaperone involved in lipid transport, complement regulation, apoptosis, endocrine secretion, and membrane protection. Elevated levels of CLU have been reported in the frontal cortex and hippocampus in AD.	[120–122]
9.	ABCA1	ABCA1 mediates cholesterol homeostasis, generation of phospholipids and immune system. The accumulation of Aβ is shown in the brain of ABCA7-deficient mice.	[123, 124]
10.	CR1	Complement Receptor-1 functions as a complement regulatory protein and helps in regulating the immune system. CR1 alteration is associated with increased cerebrospinal fluid (CSF) Aβ42 and vascular amyloid deposition.	[125, 126]
11.	CD33	CD33 mediates cell-cell interaction, inhibits immune cell functions and regulates cell growth and survival via promotion of apoptosis. CD33 contributes to the pathogenesis of AD by impairing microglia-mediated clearance of Aβ.	[127, 128]
12.	MS4A	MS4A regulates immunity and calcium influx. MS4A mediates AD pathogenesis via Aβ generation, tau phosphorylation, and apoptosis by altering calcium homeostasis.	[129, 130]
13.	BIN1	Bridging Integrator-1 regulates the immune response, synaptic vesicle endocytosis, apoptosis, intracellular APP trafficking and clathrin-mediated endocytosis. BIN1 knockdown suppresses tau-mediated neurotoxicity.	[131–133]
14.	CD2AP	CD2AP mediates regulation of the cytoskeletal structure, cell adhesion, receptor-mediated endocytosis, cytokinesis, apoptosis and intracellular trafficking. Suppression of CD2AP expression altered Aβ levels and decreased Aβ42/Aβ40 ratio.	[134, 135]
15.	PICALM	PICALM regulates intracellular trafficking and clathrin-mediated endocytosis. Knockdown of PICALM regulated APP internalization and decreased Aβ production, thus acting as a major regulator of brain Aβ production, APP internalization, and amyloid plaque load.	[136, 137]
16.	EPHA1	EPHA1 mediates synapse formation, chronic inflammation, and immune function. Association of EPHA1 variants with AD progression is well known.	[138, 139]
17.	INPP5D	INPP5D is a chief mediator of cytokine signaling and relates to increased late-onset AD.	[140]
18.	PTK2B	PTK2B is involved in activation of MAP kinase signaling pathway and calcium-induced regulation of ion channels. Fyn kinase inhibition of PTK2B improved the learning and memory impairment in AD mice.	[141, 142]
19.	SLC24A4/RIN3	SLC24A4/RIN3 is involved in neural development, lipid metabolism, and endocytic pathway. Association of SLC24A4 with methylation and brain DNA methylation is responsible for AD pathology.	[143–147]
20.	ADAM10	In Tg2576 AD mice, ADAM10 mutations were shown to increase plaque load and Aβ levels and decrease hippocampal neurogenesis.	[148]
21.	PLD3	Phospholipase D3 is highly expressed in the brain and is involved in epigenetic modifications, signal transduction, cell differentiation and neurotransmission. PLD3 is associated with APP processing and its over expression has been seen in AD patients. Accumulation of PLD3 on neuritic plaques in AD brains suggested its involvement in AD pathology.	[149–151]
22.	UNC5C	Neurons with UNC5C disease variant overexpression are more prone to Aβ-mediated cell death.	[152]