Wednesday, May 8, 2024
5/8/2024
PROJECT SUMMARY Alzheimer’s Disease (AD) is the most prevalent form of late-onset dementia, known for the presence of amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau. There is a portion of patients with AD who develop symptoms before the age of 65, known as early-onset autosomal dominant AD (ADAD), caused by mutations in the presenilin-1 (PSEN1) gene. A specific kindred of these patients was identified for having PSEN1 E280A mutations in Colombia, leading to mild cognitive impairment in their early 40s and dementia by late 40s. One patient from this kindred interestingly did not develop any memory deficits until she was in her 70s. Postmortem analyses showed that in addition to her PSEN1 E280A mutation, she also was homozygous for a mutation in her APOE3 gene, known as the Christchurch mutation (APOE3cc). Apolipoprotein E (APOE) is a lipid transporter that is expressed by astrocytes and microglia in the central nervous system and is the most common risk factor for AD. Ultimately, a better understanding of how this mutation yields resilience against ADAD could be a promising therapeutic target for AD. First, we created a mouse model of human APOE3cc to replicate the patient’s rare homozygous mutation in mice. We leveraged single nuclei RNA sequencing (snRNAseq) to elucidate which cell types could be responsible for APOE3cc’s resilience. The snRNAseq data implicated both microglia and astrocytes as regulators of APOE3cc’s neuroprotection. In microglia, our data showed that ApoEcc/cc+P301S mice significantly downregulated several interferon genes. High levels of type-I interferons in the CNS, present in both aging and neurodegeneration, have been associated with detrimental effects on cognition. In astrocytes, ApoEcc/cc+P301S mice showed reprogramming of mitochondrial and antioxidant genes. Oxidative stress and neurodegeneration are inextricably linked, and having increased antioxidant genes could explain downstream resiliency in the patient. Additionally, previous studies have linked oxidative stress to activation of the interferon pathway. I hypothesize that the combination of microglial interferon suppression and astrocytic antioxidant reprogramming protect against tau-mediated dysfunction in the ApoE3cc/cc mice. To test this hypothesis, we aim to determine the following: 1) determine the relationship of the interferon response in ApoE3cc/cc microglia to neuronal health and neurite outgrowth. 2) analyze the ApoE3cc/cc astrocytic mitochondrial, antioxidant, and metabolic response to tauopathy. Both aims will utilize a combined in vivo and in vitro approach.
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