Tau and mTOR: The Hotspots for Multifarious Diseases in Alzheimer's Development

Abstract

The hyperphosphorylation of tau protein and the overexpression of mTOR are considered to be the driving force behind Aβ plaques and Neurofibrillay Tangles (NFT's), hallmarks of Alzheimer's disease (AD). It is now evident that miscellaneous diseases such as Diabetes, Autoimmune diseases, Cancer, etc. are correlated with AD. Therefore, we reviewed the literature on the causes of AD and investigated the association of tau and mTOR with other diseases. We have discussed the role of insulin deficiency in diabetes, activated microglial cells, and dysfunction of blood-brain barrier (BBB) in Autoimmune diseases, Presenilin 1 in skin cancer, increased reactive species in mitochondrial dysfunction and deregulated Cyclins/CDKs in promoting AD pathogenesis. We have also discussed the possible therapeutics for AD such as GSK3 inactivation therapy, Rechaperoning therapy, Immunotherapy, Hormonal therapy, Metal chelators, Cell cycle therapy, γ-secretase modulators, and Cholinesterase and BACE 1-inhibitors which are thought to serve a major role in combating pathological changes coupled with AD. Recent research about the relationship between mTOR and aging and hepatic Aβ degradation offers possible targets to effectively target AD. Future prospects of AD aims at developing novel drugs and modulators that can potentially improve cell to cell signaling, prevent Aβ plaques formation, promote better release of neurotransmitters and prevent hyperphosphorylation of tau.

Keywords: Alzheimer's disease (AD); Aβ modulators; Aβ plaques; NFT's; hyperphosphorylation; mTOR; tau.

Figure 1

Interplay between mTOR, Aβ and Tau in Alzheimer's disease. mTOR is activated by the activation of a number of upstream components (PI3-K/Akt, GSK3, AMPK, IGF-1) in a sequence specific pathway. Activation of mTOR results in the activation of downstream components (4EBP1 and p70S6K1). Both 4EBP1 and p70S6K1 initiate their cascades ultimately causing hyperphosphorylation of tau, leading to the formation of PHF's and NFT's. mTOR leads to the accumulation of Aβ plaques by inhibiting autophagy. Accumulated Aβ further induces tau phosphorylation and mTOR activation. Additionally, Immune dysfunction, blood-brain barier dysfunction, upregulated Cdk5, and interlukins also contribute to AD. Formations of NFT's and Aβ plaques give rise to AD symptoms. IGF, Insulin Growth Factor; TSC1/TSC2, Tuberous Sclerosis Complex1/2; IRS, Insulin Receptor Substrate; IR, Insulin Resistance; p70S6K1, p70 ribosomal S6 Kinase1; PHF's, Paired Helical Filaments; NFT's, Neurofibrillary Tangles, p, phosphorylation; p-p, hyperphosphorylation; PI3-K, phosphoinositide 3-kinase; AMPK, AMP-activated protein kinase; GSK3, Glycogen Synthase Kinase.

Figure 2

Therapeutic approaches in Alzheimer's disease: GSK3 Inactivation therapy: Neuroprotective compounds such as curcumin modulates PI3K/Akt/GSK3β pathway, leading to inactivation of tau hyperphosphorylation. Rechaperoning therapy: Modulation of HSPGs-Aβ interaction by heparanase; PPIases (Peptidyl-prolylcis/trans isomerases (PPIases) catalyzes the tau and APP from cis to trans forms, perturbing the amylodogenesis of Aβ. Antioxidant and Deacetylation Therapy: Resveratrol activates AMPK pathway which is in turn activates SIRT1, preventing tau from hyperphosphorylation by deacetylation. Hormonal therapy: E2(17β-estradiol) modulates the APP processing by activation of estrogen receptor β; Non-steroidal anti-inflammatory drugs (NSAIDs)/γ-secretase modulators (GSMs) and peroxisome proliferator-activated receptor-gamma (PPARγ) agonists regulate β-secretase by triggering APP through activated immune response. Metal chelating agents (Cloquinol, Cu, Zn, and Fe) are used to prevent the Aβ aggregation and amyloid formation. Cell cycle therapy: Cdk5 inhibitor functions as a neuroprotectant by preventing the proteolysis of p35–p25 pathogenic form. Cholinesterase inhibitor drugs maintain the level of acetylcholine in neuronal cells by inhibiting the enzymes from breakdown of the acetylcholine. Immunotherapy: Active and passive immunization is achieved against AD by using Aβ-42 with an adjuvant and anti-Aβ-42 (Sc-Fv&mAB), respectively. mTOR inhibitors: Rapamycin/rapalogs inhibit mTOR activity which in turn inhibits AD progression by suppressing hyperphosphorylation of tau and by promoting autophagy.