Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease
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REVIEW
Cerebral blood flow decrease as an early pathological mechanism in Alzheimer’s disease Nils Korte1 · Ross Nortley1 · David Attwell1 Received: 23 June 2020 / Revised: 15 August 2020 / Accepted: 15 August 2020 © The Author(s) 2020
Abstract Therapies targeting late events in Alzheimer’s disease (AD), including aggregation of amyloid beta (Aβ) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event in AD is a decrease of cerebral blood flow (CBF). This is caused by constriction of capillaries by contractile pericytes, probably evoked by oligomeric Aβ. CBF is also reduced by neutrophil trapping in capillaries and clot formation, perhaps secondary to the capillary constriction. The fall in CBF potentiates neurodegeneration by upregulating the BACE1 enzyme that makes Aβ and by promoting tau hyperphosphorylation. Surprisingly, therefore, CBF reduction may play a crucial role in driving cognitive decline by initiating the amyloid cascade itself, or being caused by and amplifying Aβ production. Here, we review developments in this area that are neglected in current approaches to AD, with the aim of promoting novel mechanism-based therapeutic approaches. Keywords Alzheimer’s · Cerebral blood flow · Capillary · Amyloid β · Pericyte · Neutrophil
Introduction Thirty years of research have given us a broad understanding of many mechanisms contributing to Alzheimer’s disease [99], but over 400 clinical trials of drugs targeting these pathways have largely failed to reduce cognitive decline [47, 109, 136]. Identification of the amyloid β protein (Aβ) as the major component of amyloid plaques, together with genetic evidence, initially indicated that dysfunction of the processing of amyloid precursor protein (APP) was the cause of Aβ plaque deposition and downstream tau tangle formation and neuronal dysfunction [59]. Subsequent work led to the conclusion that the level of soluble Aβ oligomers, and of hyperphosphorylation of the cytoskeletal protein tau that is induced by Aβ [62, 91], correlated better with cognitive decline than did plaque level [7, 57, 89, 123].
Nils Korte and Ross Nortley contributed equally. * David Attwell [email protected] 1
Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
There are established mechanisms by which Aβ oligomers and hyperphosphorylated tau can contribute to neuronal dysfunction and cognitive decline before synaptic and neuronal damage, and even before Aβ plaque and tau tangle deposition (Fig. 1). Aβ oligomers reduce glutamate uptake [92, 94, 199]. This raises the extracellular glutamate level and increases neuronal excitability [19, 20], which alters synaptic plasticity [92, 94] and in extremis may induce excitotoxicity [60]. Tau phosphorylation leads to soluble tau relocating from axonal microtubules into dendritic spines, where it alters postsynaptic glutamate receptor trafficking or anchoring
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