Impaired microglial TYROBP/DAP12 signaling exacerbates cortical cholinergic and noradrenergic axonal degeneration in Aβ amyloidosis

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TREM2-TYROBP/DAP12 signaling is critical for microglial activation, and monoallelic hypofunctional TREM2 mutations aggravate amyloid-β (Aβ) pathology and increase the risk for Alzheimer’s disease (AD). In contrast, excessive microglial activation promotes synaptic loss and neurodegeneration, suggesting that the microglia exert dual roles in AD pathogenesis. In addition to imbalances in excitatory and inhibitory networks, dysregulation of neuromodulatory systems contributes to the clinical symptoms of AD. Basal forebrain cholinergic and locus coeruleus noradrenergic neurons extend long axons to the cerebral cortex and modulate various cognitive functions. These subcortical neurons degenerate early in AD, although the underlying mechanisms remain elusive. Here, we aimed to examine the effects of TYROBP/DAP12 knockout on the integrity of cholinergic and noradrenergic neurons in the amyloid precursor protein (APP) knock-in mouse model of Aβ pathology ( App NLGF ). In the cerebral cortex of App NLGF male mice, both glutamatergic and GABAergic axons and/or pre-synapses were enlarged around Aβ plaques and showed accumulation of phospho-tau, such as p-tau217. In contrast, axonal projections from subcortical cholinergic and noradrenergic neurons decreased in widespread cortical areas, which were not confined to peri-plaque areas and seemed to lack prominent phospho-tau accumulation. Tyrobp/DAP12 knockout in App NLGF male mice attenuated microglial activation, increased p-tau217 accumulation in peri-plaque glutamatergic/GABAergic axons and/or pre-synapses and exacerbated axonal degeneration of subcortical cholinergic and noradrenergic neurons. In brain regions with relatively low Aβ burden, Tyrobp/DAP12 knockout alone did not induce axonal degeneration. These results suggest that, besides preventing p-tau accumulation in peri-plaque synapses of cortical excitatory/inhibitory neurons, TYROBP/DAP12 signaling may play an important role in protecting axonal projections of subcortical neuromodulatory neurons to the cerebral cortex from Aβ-mediated toxicity.

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