Amyloid β induces interneuron-specific changes in the hippocampus of APPNL-F mice

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and amyloid-beta (Aβ) 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 Aβ 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 Aβ 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 Aβ-related inflammatory effects on neurons.

Knock-in models related to Alzheimer’s disease: synaptic transmission, plaques and the role of microglia

“…Moreover, the present recordings were in the presence of a GABAergic antagonist, which greatly decreased the effects reported in vivo. It should, however, be noted that we do not see alterations in spontaneous GABAergic IPSCs, either here in App knock-in mice, or previously in transgenic mice [10], which is consistent with the observation that palvalbumin-positive interneurones, despite showing some neuritic dystrophy, are otherwise normal in App NL-F mice [48]. Thus, we would not suggest that we could assess the overall physiological network effects of Aβ in the present study but can be confident about the changes seen in individual synapses.…”

The “Loss” of Perineuronal Nets in Alzheimer's Disease: Missing or Hiding in Plain Sight?

“…Although postmortem human AD brain tissue shows a significant decrease in the abundance of WFA + PNN matrices, one of the earliest PNN characterization studies in the APP/PS1 mouse model of Aβ overexpression showed a significant increase in hippocampal WFA + labeling of parvalbumin neurons as well as a corresponding increase in PNN protein abundance (i.e., neurocan, brevican, link protein, TnR) ( Table 2 ) (Végh et al, 2014 ). In contrast to this finding, two additional mouse lines of Aβ overexpression, Tg2576/APPsw and APP NL−F mice, showed no change in hippocampal PNN abundance or distribution compared to controls (Morawski et al, 2010b ; Sos et al, 2020 ). Further, the abundance of amyloid plaque formation and degree of gliosis in Tg2576/APPsw mice occurred independently of the density and laminar distribution of the PNNs themselves (Morawski et al, 2010b ).…”

The Role of Extracellular Matrix in Human Neurodegenerative Diseases

“…Chondroitin sulfate proteoglycans also protect against soluble β-amyloid: cortical neurons with perineuronal nets resist amyloid protein neurotoxicity in dissociated cultures [ 103 , 113 , 114 ]. This evokes interneuron-specific changes in the brain circuit: parvalbumin-containing interneurons selectively resisted β-amyloid-induced cell damage in an Alzheimer’s disease transgenic mouse model [ 115 ]. The proposed mechanism behind perineuronal nets’ ability to protect neurons is their capacity to bind metal ions which react with free radicals [ 104 ] to trigger and maintain oxidative stress.…”