Figure 2.

The main neural cell types origins, and the effects of Aβ₄₂-os accumulation without or with an added calcilytic. Top left: During development and in the adult, neurogenesis starts from NSCs that self-renew while giving birth to neurons and glial progenitors. From the latter (also named NG2 cells) stem both astrocytes and oligodendrocytes. All these cell types express the CaSR (see the text for details). Top right: When Aβ₄₂-os start accumulating in the brain tissues they soon block the NSCs self-renewal and differentiation of both neurons and oligodendrocytes from their respective precursors. The interactions of Aβ₄₂-os with the CaSRs (yellow ovals) elicits a surplus production/release of Aβ₄₂-os from neurons and astrocytes, of NO and VEGF-A from astrocytes, and of MBP and Aβ₄₂-os (not shown) from oligodendrocytes. All these toxic compounds together with later appearing p-Tau-os (not shown), microglial proinflammatory cytokines, and hypoxia/ischemia due to damaged micro vessels eventually cause an increasing death of neurons and oligodendrocytes (flanking skull and crossbones). Bottom center: The addition of calcilytic NPS 2143 (short termed here as NPS) thwarts all of the toxic effects elicited by Aβ₄₂-os•CaSR signaling like surplus secretion and diffusion of additional Aβ₄₂-os, NO, and VEGF-A, hindered differentiation of NSCs, and most of all, the death of neurons and oligodendrocytes, vascular damage, the later p-Tau-os appearance, and likely microglial activation (the latter two not shown). The findings on neurons and astrocytes indicate the feasibility of calcilytics as anti-LOAD therapeutics capable of halting Aβ₄₂-os self-promoting and self-maintaining mechanisms (Dal Prà et al., 2015a).