Evaluation of altered cell-cell communication between glia and neurons in the hippocampus of 3xTg-AD mice at two time points

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease and the most common form of dementia. AD is characterized by progressive memory loss and cognitive decline, affecting behavior, speech, and motor abilities. The neuropathology of AD includes the formation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles of phosphorylated tau, as well as neuronal loss. Although neuronal loss is a primary hallmark of AD, non-neuronal cell populations are known to maintain brain homeostasis and neuronal health through neuron-glia and glial cell crosstalk via chemical messengers. To investigate altered glia-neuron communication in the presence of amyloid-β and tau pathology, we generated snRNA-seq data from the hippocampus of 3xTg-AD mice at 6 and 12 months and age-matched wild-type littermates. We predicted altered glia-neuron interactions between senders (astrocytes, microglia, oligodendrocytes, and OPCs) and receivers (excitatory and inhibitory neurons) across time points. We further investigated these interactions through pseudo-bulk differential expression, functional enrichment, and gene regulatory analyses. We anesthetized and perfused 3xTg-AD mice (B6;129-Tg(APPSwe,tauP301L)1Lfa Psen1tm1Mpm/Mmjax: JAX MMRRC Stock# 034830) and wild-type littermates before dissecting brain regions to obtain hippocampal samples. We isolated nuclei from the left hippocampus of 12 female mice (6 3xTg-AD, 6 wild-type) from two time points (6 and 12 months; n = 6 per time point). The 3xTg-AD mouse model exhibits amyloid-β and tau pathology occurring as early as 6 and 12 months, respectively.