Neurobiology of Alzheimer′s disease

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disease, the most common among the dementing illnesses. The neuropathological hallmarks of AD include extracellular β-amyloid (amyloid precursor protein (APP) deposits, intracellular neurofibrillary tangles (NFT)), dystrophic neuritis and amyloid angiopathy. The mismetabolism of APP and the defective clearance of β amyloid generate a cascade of events including hyperphosphorylated tau (τ) mediated breakdown of microtubular assembly and resultant synaptic failure which results in AD. The exact aetiopathogenesis of AD is still obscure. The preeminent hypotheses of AD include amyloid cascade hypothesis and tau hyperphosphorylation. The amyloid hypothesis states that extracellular amyloid plaques formed by aggregates of Aβ peptide generated by the proteolytic cleavages of APP are central to AD pathology. Intracellular assembly states of the oligomeric and protofibrillar species may facilitate tau hyperphosphorylation, disruption of proteasome and mitochondria function, dysregulation of calcium homeostasis, synaptic failure, and cognitive dysfunction. The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs. Vascular hypothesis is also proposed for AD and it concludes that advancing age and the presence of vascular risk factors create a Critically Attained Threshold of Cerebral Hypoperfusion (CATCH) which leads to cellular and subcellular pathology involving protein synthesis, development of plaques, inflammatory response, and synaptic damage leading to the manifestations of AD. Multiple other aetiological and pathogenetic hypotheses have been put forward including genetics, oxidative stress, dysfunctional calcium homeostasis, hormonal, inflammatory-immunologic, and cell cycle dysregulation with the resultant neurotransmitter dysfunctions and cognitive decline. The available therapeutic agents target only the neurotransmitter dysfunction in AD and agents specifically targeting the pathogenetic mechanisms like amyloid deposition and tau hyperphosphorylation might provide a definite therapeutic edge.

Molecular Pathogenesis of Alzheimer's Disease: An Update

“…This postulate dictates that acetylcholine and its receptors, especially (α7) 5 are considered as neuroprotective by modulating glutamatemediated neuronal excitability [21,22] . In AD abnormalities in glutamatergic, neurotransmission is initially observed at the entorhinal cortex (EC), which is followed by further neurotransmission defects in the hippocampus, amygdala, frontal cortex, and parietal cortex [23] .…”

Re-mention of an old neurodegenerative disease: Alzheimer’s disease

“…However, A cascade combining with tau hyperphosphorylation is still the major regarded pathogenetic mechanism [26].…”

The Recent Updates of Therapeutic Approaches Against Aβ for the Treatment of Alzheimer's Disease

“…A number of studies have implied a close relationship of the mechanism of Ab protein neurotoxicity and Ab aggregation (Mattson et al, 1993). On the basis of the amyloid cascade hypothesis, Ab protein aggregation and formation of insoluble plaques trigger a cascade of deleterious changes: facilitating tau hyperphosphorylation, disruption of proteasome and mitochondria function, dysregulation of calcium homeostasis, synaptic failure, and cognitive dysfunction, resulting in neuronal death and thus causing AD (Mohandas et al, 2009). An increase of the Ab 42/40 protein ratio, rather than the changes in the absolute level of Ab42, was identified as pathogenic, and triggers of deleterious events leading to the disease (Bentahir et al, 2006).…”