Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer’s Disease Associates with Upregulated Angiopoietin and Downregulated Hypoxia-Inducible Factor

Abstract

Background: Vascular pathology is a common feature in patients with advanced Alzheimer’s disease, with cerebral amyloid angiopathy (CAA) and microvascular changes commonly observed at autopsies and in genetic mouse models. However, despite a plethora of studies addressing the possible impact of CAA on brain vasculature, results have remained contradictory, showing reduced, unchanged, or even increased capillary densities in human and rodent brains overexpressing amyloid-β in Alzheimer’s disease and Down’s syndrome. Objective: We asked if CAA is associated with changes in angiogenetic factors or receptors and if so, whether this would translate into morphological alterations in pericyte coverage and vessel density. Methods: We utilized the transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid precursor protein which develop severe CAA in addition to parenchymal plaques. Results: The main finding of the present study was that CAA in Tg-ArcSwe mice is associated with upregulated angiopoietin and downregulated hypoxia-inducible factor. In the same mice, we combined immunohistochemistry and electron microscopy to quantify the extent of CAA and investigate to which degree vessels associated with amyloid plaques were pathologically affected. We found that despite a severe amount of CAA and alterations in several angiogenetic factors in Tg-ArcSwe mice, this was not translated into significant morphological alterations like changes in pericyte coverage or vessel density. Conclusion: Our data suggest that CAA does not impact vascular density but might affect capillary turnover by causing changes in the expression levels of angiogenetic factors.

Multi-omics analysis revealed the role of CCT2 in the induction of autophagy in Alzheimer’s disease

“…This suggests that the downregulation of CCT2 may be a cause of AD. It has been proven that the accumulation of amyloid protein can affect the production of angiogenic factors ( Skaaraas et al, 2021 ).…”

High affinity of β-amyloid proteins to cerebral capillaries: implications in chronic lead exposure-induced neurotoxicity in rats

“…It is, thus, highly possible that chronic Pb exposure in the current study may cause the damage to the BBB, which in turn exacerbates the Aβ-capillary binding. Since the high affinity of Aβ 40 to cerebral capillaries is due to surface binding, intracellular uptake, or both, immunogold labeling of Aβ with electron microscopy is needed to explain this high affinity by characterizing the subcellular location of Aβ [ 54 ]. Alternatively, stimulated emission depletion (STED) microscopic technique, which provides superior imaging performance, can be utilized for the same purpose: colocalization of Aβ with endothelial luminal markers such as carbonic anhydrase IV (CA IV) [ 18 ] would differentiate the “binding” and “uptake”.…”

Impaired astrocytic Ca2+ signaling in awake-behaving Alzheimer’s disease transgenic mice

“…For norepinephrine imaging experiments, mice were injected with ssAAV-9/2 -hSyn1 -GRAB-NE1m-WPRE-hGHp(A) (University of Zürich Viral Vector Facility). To visualize Aβ plaques, 7 mg/g methoxy-X04 ( Skaaraas et al, 2021 ) dissolved in 0.1 M phosphate buffer saline (PBS) was injected intraperitoneally 24 hr prior to imaging. Also, WT littermates were injected with methoxy-X04 to rule out any confounding effects in one of the groups.…”