Genetic context controls microglia‐induced neuronal damage in Alzheimer’s disease

Abstract

AbstractBackgroundThe activation of microglia and the loss of synapses have emerged as key events in Alzheimer’s disease (AD) progression, yet the relationship between these processes is not clear. Previous studies suggest genetic variation controls microglial activation in AD mouse models, so we evaluated how the elimination of brain microglia influenced synapses on hippocampal pyramidal cells across two genetically distinct AD mouse models.MethodUsing a viral approach, we labeled hippocampal neurons that project to the frontal cortex by expressing GFP in young (3m) inbred C57BL/6J and genetically distinct PWK/PhJ female mice with or without a transgenic (APP/PS1) allele that drives amyloid pathology. At 4m we placed half of the mice on diet formulated with CSF1R inhibitor PLX5622 to deplete brain microglia. At 8m, a time when plaque pathology is present in transgenic mice, we examined cognition using the delayed spatial task. We then analyzed the density and morphology of spines across multiple dendritic domains, as well as amyloid plaques and markers of disease‐associated (DAM) and interferon responding (IRM) states of IBA1+ microglia.ResultWhile spatial cognition was unaffected by PLX5622, we identified B6.APP/PS1 as susceptible and PWK.APP/PS1 as resilient to cognitive deficits at 8m. Across both strains, PLX5622 depleted hippocampal microglia but did not affect amyloid plaques. In contrast, we observed strain differences in spine synapse density and morphology. Compared to spine stability across PWK wild‐type (WT) and APP/PS1 mice, we measured increased density of small spines in B6.APP/PS1 mice (compared to WT). B6.APP/PS1 mice showed reduced spine density with PLX5622, whereas PWK.APP/PS1 mice remained unaltered. These changes in spine density corresponded to DAM being resistant to depletion with PLX5622 in APP/PS1 mice (especially B6), whereas IRM were susceptible, suggesting a neuroprotective role for IRM.ConclusionWe show here that genetic context determines how synapses on CA1 projection neurons respond to the depletion of brain microglia and AD transgenes. Since PWK.APP/PS1 are resistant to hippocampal neuronal damage with robust microglia activation, this strain can be leveraged to further study mechanisms of resilience to AD cognitive deficits and neuropathological damage that can be harnessed for better AD therapeutic treatments.