Title:Targeting Human Astrocytes' Calcium-sensing Receptors for Treatment of Alzheimer's Disease
VOLUME: 23 ISSUE: 33
Author(s):Anna Chiarini, Ubaldo Armato*, James F. Whitfield and Ilaria Dal Pra
Affiliation:Human Histology & Embryology Unit, University of Verona Medical School, Verona, Venetia, Human Histology & Embryology Unit, University of Verona Medical School, Verona, Venetia, National Research Council of Canada, Ottawa, Ontario, Human Histology & Embryology Unit, University of Verona Medical School, Verona, Venetia
Keywords:Alzheimer's disease, calcium-sensing receptor, calcilytics, amyloid-β, amyloid precursor protein, human astrocytes, vascularendothelial
growth factor-A, tau protein.
Abstract:Understanding the pathophysiology of Alzheimer's disease (AD) in the principal human neural cells is
necessary for finding therapeutics for this illness. To help do this, we have been using freshly cultured functionally
normal cerebral cortical adult human astrocytes (NAHAs) and postnatal neurons. The findings show that
amyloid-β oligomers (Aβ-os) binding to calcium-sensing receptors (CaSRs) on NAHAs and neuron surfaces
trigger signals capable of driving AD pathogenesis. This Aβ•CaSR signalling shifts the amyloid precursor protein
(APP) from its α-secretase shedding producing neurotrophic/neuroprotective soluble (s)APPα to its β-secretase
cleaving engendering AD-driving Aβ42/Aβ42-os peptides. Aβ•CaSR signalling in NAHAs also drives the release
of toxic hyper-phosphorylated Tau proteins in exosomes, and of nitric oxide, and VEGF-A. These several harmful
agents comprise the neuron-killing machinery, driving the very slowly spreading AD neurocontagion. VEGF-A
over-secretion from Aβ-exposed blood vessel-attached astrocytes induces a functional magnetic resonance imaging-
detectable hippocampal neoangiogenesis which indicates approaching AD in amnestic minor cognitive impairment
(aMCI) patients. Most important in AD's regard, selective allosteric CaSR antagonists (calcylitics)
added to Aβ42/Aβ42-os-exposed NAHAs (or to human neuron cultures) rescue the extracellular shedding of neurotrophic/
neuroprotective sAPPα and suppress all the neurotoxic effects of Aβ•CaSR signalling even when multiple
microglial cytokines are also present. Therefore, since the multipotent calcilytics would be reasonably safe
and inexpensive drugs for humans, it is worthwhile testing them as AD therapeutics in clinical trials especially in
persons in the earliest detectable stages of AD neuropathology progression such as aMCI.
