MOLECULAR PATHOGENESIS OF ALZHEIMER'S DISEASE: THE CENTRAL ROLE OF AMYLOID AND TAU PROTEINS

Abstract

Background: Alzheimer's disease (AD) is a major cause of dementia across the globe, imposing a huge social, clinical, and economic burden. Amyloid-β (Aβ) plaques (extracellular¬¬¬) and hyperphosphorylated tau (intracellular) are central neuropathological hallmarks according to the current knowledge of its mechanistic understandings. Discussion: Hypothetically, the disease pathology starts from cleavage of amyloid precursor protein (APP). Amyloidogenic pathway (β- and γ-secretase cleavage) of APP give rise to Aβ, competing with the non-amyloidogenic pathway (α-secretase). The aggregations of Aβ isomerases to form oligomers and fibrils, which disturb neuronal Ca2+ homeostasis, induce mitochondrial and oxidative stress, and trigger neuroinflammatory responses of astrocytic & microglial cells. In parallel, tau protein undergoes hyperphosphorylation, abbreviation and misfolds to paired helical filaments, propagates between neurons in a prion-like fashion, ultimately impairing axonal transport and synaptic integrity. Evidences support cross-talk between Aβ and tau pathology rather than separate independent incidents. Accumulation of Aβ accelerates tau pathology by shared kinases like; GSK3β and CDK5 and calcium signaling dysregulation. For timely diagnosis modern-day research incorporates RNA editing, post-translational modifications, lipid raft biology, multi-omic profiling and proteostasis networks. Clinically, anti-amyloid immunotherapies and strategies featuring tau haven’t shown complete success, suggesting need of combined approaches addressing amyloid, tau and neuroinflammatory factors. Conclusion: This study emphasizes that amyloid-tau axis not as a whole story of the disease, rather a multifactorial model including dysfunction of mitochondrial RNA and microRNA, and impaired proteostasis. Instead of treating these findings as threat, we should reconcile them with classical amyloid cascade to better understand the disease pathology.