Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease.
Alzheimer’s
Amyloid β
Capillary
Cerebral blood flow
Neutrophil
Pericyte
Journal
Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
23
06
2020
accepted:
15
08
2020
revised:
15
08
2020
pubmed:
1
9
2020
medline:
22
9
2021
entrez:
1
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32865691
doi: 10.1007/s00401-020-02215-w
pii: 10.1007/s00401-020-02215-w
pmc: PMC7666276
doi:
Substances chimiques
Amyloid beta-Peptides
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
793-810Subventions
Organisme : Wellcome Trust
ID : 219366/Z/19/Z
Pays : United Kingdom
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