Severe chronic cerebral hypoperfusion induces microglial dysfunction leading to memory loss in APPswe/PS1 mice.

Cerebral vasculature plays a key role in controlling brain homeostasis. Cerebral vasculature dysfunction, associated to irregularities in cerebral blood perfusion, has been proposed to directly contribute to Alzheimer's disease (AD) pathogenesis. More precisely, chronic cerebral hypoperfusion, which impairs brain homeostasis, was demonstrated to take place even before cognitive decline. However, the mechanisms underlying the implication of chronic cerebral hypoperfusion in AD pathogenesis remain elusive. Therefore, this study aims at investigating the role of severe chronic cerebral hypoperfusion (SCCH) in AD pathogenesis. For this purpose, SCCH was induced in young APPswe/PS1 in order to evaluate the progression of AD-like pathology in these mice. We observed that SCCH accelerated the cognitive decline of young APPswe/PS1 mice, which was associated with an increased amyloid plaque number in brain parenchyma. In addition, SCCH reduced the activity of extracellular signal-regulated kinases 1/2 (ERK1/2), which has been shown to play an important role in the adaptive responses of neurons. Importantly, SCCH impaired the function of microglial cells, which are implicated in amyloid-beta (A beta) elimination. In vitro approaches underlined the ability of a low-glucose microenvironment to decrease the general activity and phagocytic capacity of microglia. By using a new model of SCCH, our study unravels new insights into the implication of severe chronic cerebral hypoperfusion in AD pathogenesis, mainly by altering microglial cell activity and consequently A beta clearance.