ABS 067: Exploring Sex-Specific Mechanisms of Sepsis on Alzheimer’s Disease-Related Changes

Victoria Zhang ¹ ² , Mohd Tayyab ² , Vijayasree V Giridharan ² , Rodrigo Morales ³ ⁴ , Tatiana Barichello ² ⁵

¹ Rice University, Houston, TX, USA
² Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
³ Laboratory of Experimental Neurology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciuma, SC, Brazil.
⁴ Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, TX, USA.
⁵ Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile.

Van Wickle (2025) Volume 1, ABS 067

Introduction: Clinical studies reveal a link between infections and the progression of cognitive decline (Kao, 2015). However, the mechanisms through which peripheral inflammation drives cognitive decline and worsens Alzheimer’s disease (AD) remain unclear. Unraveling these pathways will enhance our understanding of disease progression and support the development of novel therapeutic strategies.
Sepsis is a life-threatening infection that can leave its survivors with long-term cognitive impairments and increases the brain’s vulnerability to neurodegeneration (Prescott, 2018). We hypothesize that systemic inflammation induced by sepsis facilitates amyloidosis in the brain and triggers pathological cascades associated with AD. This study explores the connection between sepsis, meningitis, and AD pathology using APP/PS1 transgenic mice. 50-day-old APP/PS1 mice either underwent a cecal ligation and puncture surgery (CLP) to induce peripheral infection or sham surgery. After, the brain was isolated to evaluate astrocyte density in the prefrontal cortex (PFC) and hippocampus. Immunofluorescence analysis revealed increased GFAP-positive astrocyte density in the PFC of sepsis-infected mice, suggesting glial reactivity after infection and sex-differences in this mode of AD pathogenesis. Our data suggests that sepsis-induced peripheral infection increases astrocyte density potentially through a hierarchical, sex-based mechanism.

Methods: Amyloid-β precursor protein/presenilin1 (APP/PS1) mice were obtained from Jackson Laboratory (Bar Harbor, ME, USA), containing the Swedish double mutation and presenilin-1 with the delta-E9 mutation and therefore overexpress the human Aβ precursor protein (APP). 50-day-old male (n = 6) and female (n = 4) APP/PS1 mice either underwent a cecal ligation and puncture surgery (CLP) to induce systemic infection or sham surgery. Mice were housed in facilities with controlled room temperature (25ºC), humidity (50-60%), and light/dark cycles, and were given a standard food and water diet. After, the brain was isolated to evaluate the astrocyte density in the prefrontal cortex (PFC) and hippocampus using immunofluorescence.

Results: Results identified polymicrobial sepsis to increase the density of GFAP-positive astrocytes in the PFC of male and female mice, particularly through a sex-based mechanism. Immunofluorescence analysis revealed no significant changes in astrocyte density in the hippocampus of male mice (p-value = 0.673). On the other hand, increased GFAP-positive astrocyte density was detected in the male PFC (p-value < 0.05). Similar results were observed in the female hippocampus (non-significant) and PFC (p-value < 0.05). Comparative analysis between male and female APP/PS1 mice revealed that male mice express significantly greater expression of GFAP-positive astrocytes in the hippocampus, while female mice express significantly greater expression in the PFC.

Discussion: Our findings suggest that sepsis-induced peripheral infections exacerbate AD pathology by increasing the presence of GFAP-positive astrocytes. Increased astrocyte density was only observed in the PFC; this discrepancy coincides with the early stages of amyloid pathology expression, moving hierarchically from the neocortex down towards the cerebellum over time. Essentially, this makes it plausible for greater astrocyte density to be present in one region but not another. These results pave the way for future research on sex-based mechanisms of AD pathogenesis, with implications on sex-specific therapeutics to prevent AD and cognitive decline.