A humanized Aβ mouse model reveals E4-dependent cognitive impairments, microglial activation, and cerebrovascular dysfunction

Ferguson, S. J.; Pelayo, C.; Stueland, S.; Krajack, K.; Gardley, K.; Herbert, R.; Tafoya, C.; Famiano, A.; Cullen, A. E.; Setthavongsack, N.; Woltjer, R. L.; Walker, A. E.

doi:10.64898/2026.07.28.740806

bioRxiv · 10.64898/2026.07.28.740806

A humanized Aβ mouse model reveals E4-dependent cognitive impairments, microglial activation, and cerebrovascular dysfunction

Ferguson, S. J.·Pelayo, C.·Stueland, S.·Krajack, K.·Gardley, K.·Herbert, R.·Tafoya, C.·Famiano, A.·Cullen, A. E.·Setthavongsack, N.·Woltjer, R. L.·Walker, A. E.

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Abstract

Apolipoprotein E4 (E4) increases the risk of Alzheimers disease (AD) by up to 12-fold. However, understanding of the mechanisms underlying this increased risk has been limited by a lack of preclinical models that accurately reflect the effects of E4 in the presence of humanized non-mutant amyloid-{beta} precursor protein (hA{beta}PP). Therefore, we studied novel humanized APOE and hA{beta}PP mice to investigate the contributions of the E4 genotype to cognitive, inflammatory, and vascular dysfunction, specifically comparing male and female E3/hA{beta}PP and E4/hA{beta}PP mice. E4/hA{beta}PP mice exhibited impaired nest-building behavior and novel object recognition compared with E3/hA{beta}PP mice. Microglial content was higher in E4/hA{beta}PP mice, whereas astrocyte content was not different across groups. E4/hA{beta}PP mice had greater carotid and cerebral artery stiffness, and higher collagen I content in cerebral arteries than E3/hA{beta}PP mice. Under static pressure, cerebral artery endothelium-dependent and endothelium-independent vasodilation were similar across genotypes. However, high pulse pressure selectively impaired cerebral artery endothelial function in E4/hA{beta}PP mice, with the greatest impairment observed in females. The E4/hA{beta}PP mice also exhibited higher cortical expression of Nox2 and Sod1 and elevated cerebral artery Il1b expression. As such, E4/hA{beta}PP mice exhibit convergent cognitive, inflammatory, and vascular abnormalities that recapitulate several features of AD. Elevated pulse pressure revealed an E4-dependent vulnerability of the cerebral vasculature, suggesting that vascular stress may be an important contributor to disease risk. Together, our findings support the use of the APOExhA{beta}PP model to investigate the mechanisms by which E4 promotes vascular dysfunction, neuroinflammation, and cognitive impairment in AD.

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Ferguson, S. J., Pelayo, C., Stueland, S., Krajack, K., Gardley, K., Herbert, R., Tafoya, C., Famiano, A., Cullen, A. E., Setthavongsack, N., Woltjer, R. L., Walker, A. E.. 2026-07-28. A humanized Aβ mouse model reveals E4-dependent cognitive impairments, microglial activation, and cerebrovascular dysfunction. https://doi.org/10.64898/2026.07.28.740806

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