Abstract
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-β (Aβ) 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 Aβ clearance.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, which, according to current estimates, will be affecting up to 90 million patient worldwide by 2025 [1]
In the present study we aimed to investigate the implication of severe chronic cerebral hypoperfusion in AD pathogenesis
We developed a new model of severe chronic cerebral hypoperfusion (SCCH) (Supplementary Figure 1), which was induced in young APPswe/PS1 AD mouse model
Summary
Alzheimer’s disease (AD) is the most common form of dementia, which, according to current estimates, will be affecting up to 90 million patient worldwide by 2025 [1]. Previous reports have evidenced the existence of a pathological relationship between vascular risk factors and AD [3,4,5,6,7]. It was proposed that vascular dysfunction associated to cerebral blood perfusion alterations might trigger downstream events that initiate the neurodegenerative cascade observed in AD [7, 8]. Reduced cerebral blood flow (CBF) has been associated with mild cognitive impairment (MCI), which has been proposed to be implicated in AD etiology [9,10,11,12]. Impaired CBF and glucose metabolism have been reported in AD patients [13], and in mouse models of AD [14]. Impaired cerebral blood perfusion has been suggested to take place even before cognitive decline [15]
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