Elucidating the neuronal mechanisms underlying cognitive resilience to Alzheimer's Disease - Project Summary Strategies focused on reducing pathological burden in Alzheimer’s Disease (AD) have had limited effect in reversing cognitive decline. One novel approach to treating AD may be targeting resilience-promoting factors that are recruited in the 10-15% of individuals who have normal cognition but have high levels of AD pathology upon post-mortem analysis. This resilience to AD pathology has been well-characterized clinically, but the molecular mechanisms that enable resilience are largely unknown. By using a mouse model of environmental enrichment (EE), which is known to be a potent stimulator of resilience, we recently demonstrated that EE increases activity of the Mef2 transcription factors (Mef2a, Mef2c) in cortical neurons. Overexpression of Mef2 in the absence of EE was sufficient to induce cognitive resilience in a mouse model of neurodegeneration. Motivated by this discovery, this proposal aims to (1) elucidate whether Mef2 mediates survival of specific neuronal subtypes vulnerable to AD pathology, (2) assess whether Mef2 activation may be protective, and (3) leverage human single-nucleus transcriptomic data to study molecular mechanisms of resilience in humans. AD is characterized by massive neuronal loss, and Mef2 is known to promote the survival of both excitatory and inhibitory neurons. Therefore, in Aim 1, we will test whether Mef2-mediated survival of a particular neuronal subtype is critical for inducing cognitive resilience to AD pathology. After engineering custom-tailored viral vectors to express Mef2a or Mef2c in either excitatory or inhibitory neurons, we will introduce these constructs into multiple mouse models of neurodegeneration. This will allow us to evaluate both whether a particular Mef2 paralog is critical, and whether Mef2 expression in either excitatory or inhibitory neurons is the prime determinant of cognitive resilience. The specific constructs that induce a state of cognitive resilience will be further analyzed to determine the neural activity and molecular signatures of resilience. In Aim 2, we will test whether a small molecule that activates Mef2, AR-42, is able to induce cognitive resilience in multiple mouse models of AD. As AR-42 has already successfully completed Phase I clinical trials for the treatment of hematologic malignancies and was found to be safe without any significant toxicities or adverse events, our preclinical testing could directly lead to the initiation of clinical trials to assess if Mef2 activation via AR-42 could be used in the treatment of AD. Finally, in Aim 3, we will take advantage of large existing datasets of single- nuclear RNA-sequencing (snRNA-seq) data from the prefrontal cortex of hundreds of humans to identify the gene programs and cell-types that are differentially active in cognitively resilient individuals. This proposal will advance my career by providing training in the fields of aging and AD research, while enabling the development of further skills in systems neuroscience, neuroengineering, and computational biology. It will also enable me to launch an independent research program aimed at dissecting the mechanisms underlying how the environment mediates risk and resilience to the development of age-related disorders.
