Preventing the Spread of Alzheimer’s Disease Neuropathology: A Role for Calcilytics?
James F. Whitfield,
Ilaria Dal Pra.
The “amyloid cascade hypothesis” posits that an extracellular build-up of amyloid-β oligomers
(Aβ-os) and polymers (fibrils) subsequently inducing toxic hyperphosphorylated (p)-Tau oligomers
(p-Tau-os) and neurofibrillary tangles starts the sporadic late-onset Alzheimer’s disease
(LOAD) in the aged lateral entorhinal cortex. Conversely, mutated genes cause a diffuse cerebral
Aβs/Aβ-os overproduction promoting early-onset familiar AD (EOFAD). Surplus exogenous Aβ-os
exert toxic actions at several levels. They reach the nuclei of human astrocyte-neurons teams (ANTs) to enhance the transcription
of Aβ precursor protein (APP) and β-secretase/BACE1 genes. The overexpressed APP and BACE1 proteins act
in concert with γ-secretase to overproduce endogenous Aβs/Aβ-os, of which a few enter the nuclei to upkeep Aβs overproduction,
while the rest gather in the cytoplasm, damage mitochondria, and are oversecreted. Simultaneously, extracellular
Aβ-os bind the ANTs’ calcium-sensing receptors (CaSRs) activating signalings that hinder the proteolysis and hence
favor the surplus hoarding/secretion of Aβs/Aβ-os. Overreleased Aβ-os spread, reach growing numbers of adjacent ANTs
to recruit them to overproduce/oversecrete further Aβ-os amounts via the just mentioned mechanisms. Alongside,
Aβ•CaSR signalings elicit a noxious overproduction/overrelease of nitric oxide (NO) and vascular endothelial growth factor
(VEGF)-A from ANTs’ astrocytes. While astrocytes survive the toxic onslaught, neurons die. Thus, AD progression is
driven by ceaselessly self-sustaining neurotoxic cycles, which engender first Aβ-os and later p-Tau-os that cooperatively
destroy increasingly wider cognition-related cortical areas. Notably, a highly selective allosteric CaSR antagonist (calcilytic),
like NPS 2143, does preserve human cortical postnatal HCN-1A neurons viability notwithstanding the presence
of exogenous Aβ-os by suppressing the otherwise elicited oversecretion and spread of newly synthesized Aβ-os. Therefore,
if given at minimal cognitive impairment or earlier stages, calcilytics could halt AD progression and preserve the patients’
cortical neurons, cognitive abilities, and eventually life.
Keywords: Aβ oligomers, Alzheimer, astrocyte, calcilytics, CaSR, human, neuron, Tau protein.
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