Quantitative Vascular Reconstruction of Amyloid Angiopathy in ApoA-I–Deficient APP/PS1 Mice
Button EB, Boyce GK, Wilkinson A, Stukas S, Hayat A, Fan J, Wadsworth BJ, Robert J, Martens KM, Wellington CL. ApoA-I deficiency increases cortical amyloid deposition, cerebral amyloid angiopathy, cortical and hippocampal astrogliosis, and amyloid-associated astrocyte reactivity in APP/PS1 mice. Alzheimers Res Ther 2019;11(1):44. doi: 10.1186/s13195-019-0497-9.
Background: Alzheimer’s disease (AD) is marked by amyloid-β (Aβ) plaques, neurofibrillary tangles and neurodegeneration, with many patients also showing cerebrovascular amyloid deposition known as cerebral amyloid angiopathy (CAA). Circulating high-density lipoproteins (HDL) and their major protein component apolipoprotein A-I (apoA-I) exert vasoprotective effects and have been associated with reduced AD risk and amyloid burden in experimental models.
Hypothesis: This study hypothesized that deficiency of apoA-I exacerbates amyloid deposition, cerebrovascular pathology and astrocyte reactivity in APP/PS1 transgenic mice.
Methods: The authors used APP/PS1 mice either hemizygous or deficient for apoA-I. Plasma lipids, Aβ levels and markers of inflammation were measured by ELISA and qRT-PCR. Immunofluorescence was used to quantify amyloid, vascular and astrocytic markers. Vascular morphology, including vessel diameter and tortuosity, was analyzed using Vesselucida 360 and data were reconstructed and quantified with Vesselucida Explorer. Behavioral performance was assessed by contextual and cued fear conditioning.
Results: ApoA-I deficiency significantly increased total and vascular Aβ deposition in the cortex, elevated cortical Il1b mRNA, ICAM-1, PDGFRβ and GFAP protein levels, and intensified astrocyte reactivity around Aβ-laden vessels and plaques. No effects on hippocampal amyloid or behavior were observed.
Conclusions: Loss of apoA-I amplifies cortical amyloid accumulation and cerebrovascular astrogliosis in APP/PS1 mice, supporting a protective role of apoA-I–containing HDL against amyloid pathology and astrocyte activation in AD.
