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Integrated Phylogeny of the Human Brain and Pathobiology of Alzheimer's Disease: A Unifying Hypothesis.

Neuroscience Letters 2021 April 14
The disproportionate evolutionary expansion of human cerebral cortex with reinforcement of cholinergic innervations warranted the rise in functional and metabolic load of conserved basal forebrain (BF) cholinergic system. Given that acetylcholine (ACh) regulates the properties of microtubule-associated protein (MAP) tau and promotes non-amyloidogenic processing of amyloid precursor protein (APP), the growing neocortex increased demands for ACh, while the emerging role of BF cholinergic projections in Aβ clearance entailed greater exposure of source neurons and their innervation fields to amyloid pathology and tau toxicity. The higher exposure of evolutionary most recent cortical areas to amyloid pathology of Alzheimer's disease (AD) with synaptic deficit and atrophy, therefore, might involve reduced homeostatic and protective effects of BF cholinergic projections, in addition to fall-outs of inherent processes of expanding association areas. This unifying model, thus, views amyloid pathology and loss of cholinergic cells as a quid pro quo of the allometric evolution of the human brain, which in combination with increase in life expectancy overwhelm the BF mechanisms and initiate the disease process.

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