Biology subjects

Walker, A. E.

Publications and source records attributed to Walker, A. E..

6 recordsLinked to original sources

bioRxiv2026

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

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.

physiology↗

bioRxiv2026

APOE4 genotype and old age interact to impact cerebrovascular function, brain volume, and neuroinflammation in mice

Old age and the apolipoprotein E {varepsilon}4 (APOE4) genotype are two of the greatest risk factors for late-onset Alzheimers disease (LOAD). However, the interaction between these is poorly understood, as most preclinical studies use young mice. Therefore, we assessed the interaction between APOE genotype and age across a comprehensive set of cerebrovascular and related outcomes. We performed in vivo imaging, ex vivo cerebral artery studies, behavioral tests, and molecular analyses in male and female homozygous APOE3 and APOE4 mice at [~]6 months (young) and [~]24 months (old). APOE4 interacted with old age to lead to deficits in brain volume and greater microglia content. Old APOE4 mice also exhibited greater cerebral artery vasoconstriction to endothelin-1 (ET-1) than old APOE3 mice, a response concomitant with age-and genotype-related differences in the expression of ET-1 receptors and endothelin-converting enzyme. While we found several interactions between age and APOE genotype, only age impacted cognitive function, cerebral artery endothelial function, and arterial stiffness. In summary, we found that brain volume, neuroinflammation, and ET-1-related outcomes were influenced by the interaction of APOE genotype and age, while other outcomes were affected only by age. As such, an altered ET-1 response and greater neuroinflammation may contribute to the increased risk for LOAD in APOE4 carriers.

neuroscience↗

bioRxiv2025

WSB.APP/PS1 mice develop age-dependent cerebral amyloid angiopathy, cerebrovascular deficits, and white matter damage, which are modified by humanized APOE alleles.

INTRODUCTIONGrowing evidence suggests cerebrovascular deficits, including cerebral amyloid angiopathy (CAA), play a key role in Alzheimers disease (AD) pathogenesis. However, these facets of AD are not well understood, due in part to the lack of mouse models that develop robust vascular deficits and CAA. Here, we characterize human-relevant cerebrovascular phenotypes in WSB.APP/PS1 mice with and without humanized APOE alleles. METHODSAD-relevant cerebrovascular phenotypes in WSB, WSB.APP/PS1, WSB.APOE2/2APP/PS1, WSB.APOE3/3APP/PS1, and/or WSB.APOE4/4APP/PS1 mice were characterized using immunohistochemistry, transcriptomics, positron emission tomography/computed tomography, and ex-vivo analyses. RESULTSWSB.APP/PS1 mice exhibited age-related plaque deposition and CAA, significant transcriptomic overlap with human AD, myelin deficits, cerebrovascular/metabolic uncoupling, and altered cerebrovascular morphology. Aged WSB vasculature retained vasoreactivity, but exhibited increased stiffness. Compared to APOE2, APOE4 expression in WSB.APP/PS1 mice increased CAA and plaque-associated microglial area. DISCUSSIONThese data illustrate the utility of the WSB genetic context to model CAA and uncover vascular contributions to AD. HighlightsO_LIWSB.APP/PS1 mice developed CAA with age. C_LIO_LITranscriptomic profiling revealed significant molecular overlap between human AD and WSB.APP/PS1 brains. C_LIO_LITranscriptomics and immunofluorescence suggested age-related myelin deficits in WSB.APP/PS1 brains. C_LIO_LIWSB.APP/PS1 brains exhibited neurovascular uncoupling, changes in vascular volume and surface area, and increased permeability changes. C_LIO_LIWSB.APP/PS1 cerebrovasculature was resilient to loss of responsivity with age but exhibited increased vascular stiffness. C_LIO_LIHumanized APOE {varepsilon}4 alleles significantly increased CAA and parenchymal plaque-associated microglial area in WSB.APP/PS1 mice. C_LI Research in ContextO_LISystematic review: The authors characterized WSB.APP/PS1 as a unique human-relevant model of Alzheimers Disease and explored several facets of cerebrovascular deficits. C_LIO_LIInterpretation: WSB and/or WSB.APP/PS1 mice exhibited human-relevant vascular phenotypes, including CAA, neurovascular uncoupling, increased vascular tree volume, vascular stiffness, and resilience to age-related loss of responsivity. Furthermore, the transcriptomic profile of WSB.APP/PS1 brains significantly overlaps with signatures observed in human AD. WSB.APP/PS1 brains exhibited myelin deficits with age. Furthermore, humanized APOE {varepsilon}2, {varepsilon}3, and {varepsilon}4 alleles significantly modified WSB.APP/PS1 susceptibility to CAA, plaque deposition, and plaque-associated microglial area. C_LIO_LIFuture Directions: The WSB genetic context will be leveraged to identify specific molecular mechanisms associated with cerebrovascular deficits in AD. C_LI

neuroscience↗

bioRxiv2025

Cerebral blood flow in elastin haploinsufficient and 3xTg-AD mice

Artery structural properties and Alzheimers disease (AD) pathology are individually associated with impaired cerebrovascular function; however, the interaction of these factors is unclear. Furthermore, while elastin haploinsufficient (Eln+/-) mice are known to have impaired cerebrovascular function, sex differences for this effect have not been previously studied. To answer these questions, we crossed middle-aged and old Eln+/-mice with 3xTg-AD mice. We measured cerebral blood flow (CBF) using arterial spin labeling MRI at rest and during hypercapnia to calculate cerebrovascular reactivity (CVR). We also assessed neuroinflammation by microglia and astrocyte cell counts. We found that Eln+/- mice had lower resting blood flow rate in the cerebral cortex compared with Eln+/+ mice, but Eln+/- mice had an intact hypercapnic response, resulting in better CVR compared with Eln+/+ in hippocampus. Sex did not impact resting blood flow or CVR. 3xTg-AD mice had a lower resting CBF than non-AD mice, and there was an interaction between Eln genotype and AD mutations on CVR, such that Eln+/-x 3xTg-AD mice had the poorest hippocampal CVR of all groups. Glia cell counts were highly dependent on brain region, with Eln+/- having more microglia but fewer astrocytes, while 3xTg-AD having higher both microglia and astrocytes. While sex also impacted glial cell counts, we found no interactions between sex and Eln genotype. Our results demonstrate that elastin haploinsufficiency and AD mutations individually result in lower resting CBF, and the combination of these leads to impaired CVR. NEW & NOTEWORTHYThe findings of this study demonstrate that elastin haploinsufficiency leads to lower resting cerebral blood flow, but also greater cerebrovascular reactivity. However, elastin haploinsufficiency interacts with Alzheimers disease mutations to impair cerebrovascular reactivity. These results suggest that multiple insults, such as changes to the extracellular matrix combined with genetic risk factors, are needed to impact cerebrovascular reactivity.

physiology↗

bioRxiv2025

APOE4 genotype negates the benefits of 17β-estradiol on cerebrovascular endothelial and mitochondrial function

BackgroundPostmenopausal females who carry an APOE{varepsilon}4 allele are at higher risk of late-onset Alzheimers Disease compared to age-matched APOE{varepsilon}4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive, and metabolic impairments. While estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, their cerebrovascular effects are less understood. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen on cerebrovascular endothelial and mitochondrial function. MethodsYoung female homozygous APOE{varepsilon}3 and APOE{varepsilon}4 mice (n=19-20/group; ~6 months old) fed a high-fat diet were ovariectomized (OVX), OVX and supplemented with 17{beta}-estradiol, or left intact. ResultsIn APOE{varepsilon}3 mice, OVX was associated with impaired posterior cerebral artery endothelium-dependent dilation, which was rescued by 17{beta}-estradiol. However, in APOE{varepsilon}4 mice, there was no effect of OVX or 17{beta}-estradiol on cerebral artery endothelial function. Carotid artery passive stiffness was greater with OVX and lower with 17{beta}-estradiol treatment in APOE{varepsilon}3 mice, but there was no impact of OVX or 17{beta}-estradiol in the APOE{varepsilon}4 mice. In cerebral arteries and arterioles, mitochondrial complexes I and I+II respiration were lower in APOE{varepsilon}4 mice compared with APOE{varepsilon}3 mice. 17{beta}-estradiol led to higher mitochondrial complex I respiration in APOE{varepsilon}3 but not APOE{varepsilon}4 mice. These functional differences were concomitant with group differences in mitochondrial DNA copy number, antioxidant enzymes, and pro-inflammatory factors. In contrast to other outcomes, we found that 17{beta}-estradiol treatment was associated with lower cerebral artery stiffness in APOE{varepsilon}4 but not APOE{varepsilon}3 mice. ConclusionsOverall, these results indicate that the APOE genotype modulates the impact of estrogen on the cerebral vasculature. We found that 17{beta}-estradiol enhances cerebrovascular endothelial and mitochondrial function in APOE{varepsilon}3 mice but not in APOE{varepsilon}4 mice. The results suggest that 17{beta}-estradiol supplementation has more cerebrovascular benefit for APOE{varepsilon}4 non-carriers. Novelty & SignificanceO_ST_ABSWhat is known?C_ST_ABSO_LIFemales have twice the risk of Alzheimers disease compared with males, and the APOE4 genetic variant is associated with a greater risk for Alzheimers disease compared with the APOE3 variant. C_LIO_LIThe risk for Alzheimers disease increases after menopause in females, suggesting that the loss of female sex hormones may play a role. C_LIO_LIThere are highly inconsistent results among past studies examining the interaction of APOE genotype and estrogens on cognitive function and other brain outcomes. C_LI What new information does this article contribute?Vascular outcomes were not measured in previous studies examining the interaction between APOE genotype and estrogens. As such, we aimed to determine the impact of APOE4 genotype on the cerebrovascular response to estradiol. We found that estradiol improved cerebral artery endothelial function and mitochondrial respiration in APOE3 mice following ovariectomy. In contrast, APOE4 mice were refractory to the beneficial effects of estradiol on cerebrovascular endothelial and mitochondrial function. The broader implication of this research is that APOE genotype may be a consideration when prescribing hormone replacement therapy to menopausal females due to the impact on vascular outcomes.

physiology↗

bioRxiv2025

The Impact of Age and Sex on Cerebral and Large Artery Stiffness and the Response to Pulse Pressure

Vascular aging is characterized by a tandem increase in pulse pressure and large elastic artery stiffness. Greater stiffness of the large arteries leads to elevated pulse pressure transmitted into the cerebral circulation, causing dysfunction. However, little is known in females about age-related stiffening of the arteries and the impacts of high pulse pressure on the cerebral vasculature. To examine the effects of sex and age on the cerebral artery response to pulse pressure, we studied cerebral arteries collected from young and old female and male C57BL/6 mice. Isolated cerebral arteries were exposed ex vivo to static pressure, low pulse pressure, and high pulse pressure. Exposure to high pulse pressure impaired endothelium-dependent dilation in cerebral arteries from young female and male mice, with impairments also occurring in young female cerebral arteries after exposure to low pulse pressure. In contrast, exposure to low or high pulse pressure did not impact cerebral artery endothelium-dependent dilation for old male or female mice. During exposure to high pulse pressure, young females had higher cerebral artery compliance compared with young males and old females. Old mice also had higher cerebral artery passive stiffness and aortic pulse wave velocity compared with young mice. We also found age and sex differences in arterial wall thickness, collagen and elastin content, and matrix metalloproteinase 9 expression. Taken together, young female mice have more compliant cerebral arteries, which are more susceptible to endothelial dysfunction caused by pulse pressure.

physiology↗