Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

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.

Structural and Functional Features of Developing Brain Capillaries, and Their Alteration in Schizophrenia

“…The affected cells of the NVC would fail to maintain BBB integrity resulting in leakiness, associated with homeostatic disturbance from the periphery (e.g., inflammatory mediators and cells), and blood flow reduction providing limited oxygen and nutrient supply to the brain, impairing brain maturation. This mechanism is consistent with evidence seen in other disorders such as Alzheimer ( Korte et al, 2020 ) and could explain the higher probability of neurodegenerative disorder in diabetic patients in which many vascular anomalies are observed ( Nelson et al, 2016 ). Alterations in glial cells (mainly microglia and astrocytes) could contribute to this neurovascular fragility ( Figure 1 ).…”

Microvascular Alterations in Alzheimer's Disease

“…Restoring blood flow in early stages of AD progression could limit dementia progression. Korte et al ( 2020 ) outline additional therapeutic approaches targeting blood flow. Capillary constriction via pericytes occurs via Aβ-oligomer production of ROS from pericytes and microglia and activation of endothelin A receptors that bind endothelin (a vasoconstrictor).…”

“…Capillary constriction via pericytes occurs via Aβ-oligomer production of ROS from pericytes and microglia and activation of endothelin A receptors that bind endothelin (a vasoconstrictor). Relaxing pericytes via voltage-gated calcium channel (VGCC) inhibition is a therapeutic target, with a VGCC-inhibitor (nilvadipine, normally used for hypertension) restoring cortical CBF in 13-month old Tg2576 mice, and hippocampal CBF in humans with mild-moderate AD (Paris et al, 2004b ; de Jong et al, 2019 ; Korte et al, 2020 ). Additional therapies suggested by Korte et al ( 2020 ) include preventing occluded capillaries through neutrophil targeting and anticoagulants to enhance blood flow.…”

“…Relaxing pericytes via voltage-gated calcium channel (VGCC) inhibition is a therapeutic target, with a VGCC-inhibitor (nilvadipine, normally used for hypertension) restoring cortical CBF in 13-month old Tg2576 mice, and hippocampal CBF in humans with mild-moderate AD (Paris et al, 2004b ; de Jong et al, 2019 ; Korte et al, 2020 ). Additional therapies suggested by Korte et al ( 2020 ) include preventing occluded capillaries through neutrophil targeting and anticoagulants to enhance blood flow. However, depletion of neutrophils may lead to infection, while anticlotting agents could induce hemorrhage (Korte et al, 2020 ).…”

“…Additional therapies suggested by Korte et al ( 2020 ) include preventing occluded capillaries through neutrophil targeting and anticoagulants to enhance blood flow. However, depletion of neutrophils may lead to infection, while anticlotting agents could induce hemorrhage (Korte et al, 2020 ).…”