Cerebrovascular pathology during the progression of experimental Alzheimer's disease

Abstract

Clinical and experimental evidence point to a possible role of cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse model of AD expresses human amyloid precursor protein and presenilin genes with mutations found in AD patients. It remains unknown whether amyloid deposition driven by these mutations is associated with cerebrovascular changes. 5xFAD and wild type mice (2 to 12months old; M2 to M12) were used. Thinned skull in vivo 2-photon microscopy was used to determine Aβ accumulation on leptomeningeal or superficial cortical vessels over time. Parenchymal microvascular damage was assessed using FITC-microangiography. Collagen-IV and CD31 were used to stain basal lamina and endothelial cells. Methoxy-XO4, Thioflavin-S or 6E10 were used to visualize Aβ accumulation in living mice or in fixed brain tissues. Positioning of reactive IBA1 microglia and GFAP astrocytes at the vasculature was rendered using confocal microscopy. Platelet-derived growth factor receptor beta (PDGFRβ) staining was used to visualize perivascular pericytes. In vivo 2-photon microscopy revealed Methoxy-XO4(+) amyloid perivascular deposits on leptomeningeal and penetrating cortical vessels in 5xFAD mice, typical of cerebral amyloid angiopathy (CAA). Amyloid deposits were visible in vivo at M3 and aggravated over time. Progressive microvascular damage was concomitant to parenchymal Aβ plaque accumulation in 5xFAD mice. Microvascular inflammation in 5xFAD mice presented with sporadic FITC-albumin leakages at M4 becoming more prevalent at M9 and M12. 3D colocalization showed inflammatory IBA1(+) microglia proximal to microvascular FITC-albumin leaks. The number of perivascular PDGFRβ(+) pericytes was significantly decreased at M4 in the fronto-parietal cortices, with a trend decrease observed in the other structures. At M9-M12, PDGFRβ(+) pericytes displayed hypertrophic perivascular ramifications contiguous to reactive microglia. Cerebral amyloid angiopathy and microvascular inflammation occur in 5xFAD mice concomitantly to parenchymal plaque deposition. The prospect of cerebrovascular pharmacology in AD is discussed.

Donecopride, a Swiss army knife with potential against Alzheimer's disease

“…The 5XFAD mice reproduce several major features of AD amyloid pathology, including amyloid‐induced neurodegeneration, inflammation, and synaptic and behavioural dysfunction (Crouzin et al, ; Giannoni et al, , ; Girard et al, ). In a first experiment conducted under the original B6/SJL genetic background (Giannoni et al, ; Oakley et al, ), female mice received vehicle or donecopride (1 mg·kg −1 ; i.p.) twice a week for 3 months from 10 to 22 weeks of age.…”

“…twice a week for 3 months from 11 to 22 weeks of age. The treatment started when amyloid deposits began to form in mouse brains (Giannoni et al, ; Oakley et al, ). At the end of treatment, mice were evaluated with the NOR test for long‐term memory performance.…”

Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

“…One possible reason for this failure is the structural and functional impairments of the cerebral microvasculature, that are induced by Aβ deposition, and which are important mechanisms for AD cerebrovascular damage (Dorr et al, 2012;Kimbrough et al, 2015;Sisante et al, 2019). The cerebral amyloid angiopathy, caused by the deposition of Aβ in the wall of cerebral blood vessels, not only destroys the cerebrovascular structure, but also impairs the neurovascular coupling (Lai et al, 2015;Giannoni et al, 2016;Yan et al, 2017;Hecht et al, 2018). Generally, the results suggest that under such circumstances, therapeutic strategies that attempt to enhance CBF through vasodilation, are less feasible.…”

High-Throughput Screening for Identification of Blood-Brain Barrier Integrity Enhancers: A Drug Repurposing Opportunity to Rectify Vascular Amyloid Toxicity

“…While multiple pathological alterations in AD brains could contribute to vascular dysfunction [53, 65–67], findings from AD patients’ brains and preclinical studies using AD mice models also support the disruptive effect of increased brain levels of Aβ on the integrity and function of the BBB [11, 68–70]. This breakdown in the BBB integrity was associated with uncontrolled molecular transport and solute exchange [71], and reduced expression and re-localization of TJ proteins [11, 65, 69, 70]. Accordingly, such alterations in the BBB observed in AD point toward the BBB as a target for therapeutic interventions to improve or rectify the BBB normal activity [34, 72].…”