Do Astrocytes Collaborate with Neurons in Spreading the “Infectious” Aβ and Tau Drivers of Alzheimer’s Disease?

Abstract

Evidence has begun emerging for the “contagious” and destructive Aβ₄₂ (amyloid-beta₄₂) oligomers and phosphorylated Tau oligomers as drivers of sporadic Alzheimer’s disease (AD), which advances along a pathway starting from the brainstem or entorhinal cortex and leading to cognition-related upper cerebral cortex regions. Seemingly, Aβ₄₂ oligomers trigger the events generating the neurotoxic Tau oligomers, which may even by themselves spread the characteristic AD neuropathology. It has been assumed that only neurons make and spread these toxic drivers, whereas their associated astrocytes are just janitorial bystanders/scavengers. But this view is likely to radically change since normal human astrocytes freshly isolated from adult cerebral cortex can be induced by exogenous Aβ_25-35, an Aβ₄₂ proxy, to make and secrete increased amounts of endogenous Aβ₄₂. Thus, it would seem that the steady slow progression of AD neuropathology along specific cognition-relevant brain networks is driven by both Aβ₄₂ and phosphorylated Tau oligomers that are variously released from increasing numbers of “contagion-stricken” members of tightly coupled neuron–astrocyte teams. Hence, we surmise that stopping the oversecretion and spread of the two kinds of “contagious” oligomers by such team members, perhaps via a specific CaSR (Ca²⁺-sensing receptor) antagonist like NPS 2143, might effectively treat AD.