P4‐164: APOA‐I DEFICIENCY INCREASES CORTICAL AMYLOID DEPOSITION, CEREBRAL AMYLOID ANGIOPATHY, CORTICAL AND HIPPOCAMPAL ASTROGLIOSIS AND AMYLOID‐ASSOCIATED ASTROCYTE REACTIVITY IN APP/PS1 MICE

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, leads to increased CAA and reduced cognitive dysfunction, whereas overexpression of apoA-I from its native promoter in liver and intestine has the opposite effect and lessens neuroinflammation. Similarly, acute administration of reconstituted HDL reduces soluble Aβ pools in the brain and some have observed reductions in CAA as well. In this study 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. 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 was used to assess behavior. 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. Neuroinflammatory markers including Il1b mRNA, ICAM-1 protein, PDGFRβ protein, GFAP protein and GFAP positive staining in both cortex and hippocampus were also elevated in apoA-I-deficient APP/PS1 mice. A striking observation was that astrocytes associated with cerebral vessels, in particular in vessels laden with Aβ, showed increased reactivity in APP/PS1 mice lacking apoA-I. No behavioral changes were observed. ApoA-I-containing HDL can reduce amyloid pathology and astrocyte reactivity to parenchymal and vascular amyloid in APP/PS1 mice.

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