Amyloid Beta Induces Interneuron-Specific Changes In The Hippocampus Of App(Nl-F) Mice

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and amyloid-beta (A beta) depositions generated by the proteolysis of amyloid precursor protein (APP) in the brain. In APP(NL-F) mice, APP gene was humanized and contains two familial AD mutations, and APP-unlike other mouse models of AD-is driven by the endogenous mouse APP promoter. Similar to people without apparent cognitive dysfunction but with heavy A beta plaque load, we found no significant decline in the working memory of adult APP(NL-F) mice, but these mice showed decline in the expression of normal anxiety. Using immunohistochemistry and 3D block-face scanning electron microscopy, we found no changes in GABA(A) receptor positivity and size of somatic and dendritic synapses of hippocampal interneurons. We did not find alterations in the level of expression of perineuronal nets around parvalbumin (PV) interneurons or in the density of PV- or somatostatin-positive hippocampal interneurons. However, in contrast to other investigated cell types, PV interneuron axons were occasionally mildly dystrophic around A beta plaques, and the synapses of PV-positive axon initial segment (AIS)-targeting interneurons were significantly enlarged. Our results suggest that PV interneurons are highly resistant to amyloidosis in APP(NL-F) mice and amyloid-induced increase in hippocampal pyramidal cell excitability may be compensated by PV-positive AIS-targeting cells. Mechanisms that make PV neurons more resilient could therefore be exploited in the treatment of AD for mitigating A beta-related inflammatory effects on neurons.