ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice

Abstract

Background Alzheimer’s disease (AD) is defined by amyloid beta (Aβ) plaques and neurofibrillary tangles and characterized by neurodegeneration and memory loss. The majority of AD patients also have Aβ deposition in cerebral vessels known as cerebral amyloid angiopathy (CAA), microhemorrhages, and vascular co-morbidities, suggesting that cerebrovascular dysfunction contributes to AD etiology. Promoting cerebrovascular resilience may therefore be a promising therapeutic or preventative strategy for AD. Plasma high-density lipoproteins (HDL) have several vasoprotective functions and are associated with reduced AD risk in some epidemiological studies and with reduced Aβ deposition and Aβ-induced inflammation in 3D engineered human cerebral vessels. In mice, deficiency of apoA-I, the primary protein component of HDL, increases CAA and cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute peripheral administration of HDL reduces soluble Aβ pools in the brain and some studies have observed reduced CAA as well. Here, we expand upon the known effects of plasma HDL in mouse models and in vitro 3D artery models to investigate the interaction of amyloid, astrocytes, and HDL on the cerebrovasculature in APP/PS1 mice . Methods APP/PS1 mice deficient or hemizygous for Apoa1 were aged to 12 months. Plasma lipids, amyloid plaque deposition, Aβ protein levels, protein and mRNA markers of neuroinflammation, and astrogliosis were assessed using ELISA, qRT-PCR, and immunofluorescence. Contextual and cued fear conditioning were used to assess behavior. Results In APP/PS1 mice, complete apoA-I deficiency increased total and vascular Aβ deposition in the cortex but not the hippocampus compared to APP/PS1 littermate controls hemizygous for apoA-I. Markers of both general and vascular neuroinflammation, including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, and GFAP protein, were elevated in apoA-I-deficient APP/PS1 mice. Additionally, apoA-I-deficient APP/PS1 mice had elevated levels of vascular-associated ICAM-1 in the cortex and hippocampus and vascular-associated GFAP in the cortex. A striking observation was that astrocytes associated with cerebral vessels laden with Aβ or associated with Aβ plaques showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. Conclusions ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice. Electronic supplementary material The online version of this article (10.1186/s13195-019-0497-9) contains supplementary material, which is available to authorized users.

The Amyloid-Tau-Neuroinflammation Axis in the Context of Cerebral Amyloid Angiopathy

“…Complete loss of ApoA-I increases cortical and hippocampal CAA pathology and astrogliosis in APP/PS1 mice, boosting both neuro and vascular inflammatory markers, specifically IL-1β, PDGFRβ, GFAP, and ICAM-1. These mice also showed an increase in GFAP-positive astrocytes associated with the cerebrovasculature [168]. ApoA-I could be an interesting target for a CAA-directed therapy as it was observed that APP/PS1 mice overexpressing ApoA-I or injection of ApoA-I reduced both astrogliosis and cerebral amyloid burden.…”

The Role of HDL and HDL Mimetic Peptides as Potential Therapeutics for Alzheimer’s Disease

“…On the contrary, a recent study using another transgenic mouse model of AD (Tg2576) showed that lack of APOA-I decreased both parenchymal and vascular Aβ pathology [86]. However, another recent study with APP/PS1 mice extended prior findings, in which APOA-I deficiency increased CAA and neuroinflammation as well as cortical Aβ deposition [87]. The differences between the AD animal models used and the ages of the mice studied may explain these discrepancies.…”

“…APOA-I drives the critical role of HDL in cerebrovascular endothelial damage repair and inhibition of endothelial apoptosis [136]. Overexpression of human APOA-I mitigates CAA whereas lack of APOA-I exacerbates CAA in AD mouse models [83,84,87]. Moreover, pericytes, a key component in the BBB and the neurovascular unit, have recently emerged as a crucial regulator of vessel morphology and function [137,138].…”

Alternatives to amyloid for Alzheimer's disease therapies—a symposium report

“…Epidemiological data suggest that HDL may protect against dementia, [76][77][78][79][80] and animal models show that low HDL levels lead to increased vascular amyloid and inflammation, while addition of that HDL can reduce CAA and soluble amyloid and brain Aβ levels. [81][82][83] While these studies suggest that HDL has a protective effect on cerebral vessels, key differences between mouse and human lipoprotein metabolism mean that these results need to be interpreted with caution. To understand how lipoproteins affect Aβ clearance across the arterial wall, Wellington's group has developed a bioengineered cerebrovascular model that incorporates many of the features of cerebral vessels, including an anatomically correct vascular anatomy, functional BBB, and dynamic perfusion.…”