Individual differences in cognitive resilience to AD are not explained by variation in neurogenesis in the AD-BXDs

Emily Kim

Document Type

Article

Publication Date

Summer 2022

Keywords

JMG

JAX Location

In: Student Reports, Summer 2022, The Jackson Laboratory

Abstract

In recent clinical-pathologic studies, a significant portion of the human population has been found to exhibit Alzheimer’s Disease (AD) pathology without experiencing cognitive decline (Bennett et al., 2018). Using translationally relevant mouse models and cell culture, we aim to explore why rare individuals are “resilient to AD,” or exhibit AD pathology but no clinical symptoms, as compared to those that are “susceptible” to cognitive impairment. Recent transcriptome studies conducted by the Kaczorowski lab in the AD-BXD mouse panel, which model differences in susceptibility and resilience to AD, implicated a role for enhanced neurogenesis in resilience from gene signatures in layer 5 cortical neurons. However, using immunofluorescence techniques and microscopy to quantify anti-doublecortin (DCX), a marker of neurogenesis, we found no evidence of neurogenesis in cortical layer 5 neurons from either resilient and susceptible mice. While DCX was found in the hippocampus, no statistical differences were seen in hippocampal expression in different AD-BXD lines, implying that resilience to the AD mutation in AD-BXDs is not driven by changes in cortical or hippocampal neurogenesis. However, we did find that neurogenesis expression has a strong negative correlation with CFM scores across the ADBXD mouse panel, which nominates it as a target for precision medicine. After ruling out neurogenesis as a potential driver of AD resilience, we examined an alternative hypothesis, that differences in neuronal excitability might underlie resilience to AD. To monitor neuronal activity, we optimized the use of microelectrode array (MEA) plates to record cell electrical signal, spike frequencies, bursts, and synchrony on mouse mixed cortical culture, in hopes of eventually investigating the role of resilient genes on neuronal activity with knockdown techniques.

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