Tau binding protein CAPON induces tau aggregation and neurodegeneration

Abstract

To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the App NL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer’s disease (AD) pathogenesis, CAPON was overexpressed in the brain of App NL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer’s Disease-Related Pathological Progression in the Hippocampus of AppNL-G-F/NL-G-F Mice

“…In the present study, astaxanthin supplementation to the experimental mice started from 5-to-6 weeks old before Ab deposition started, and the mice were sacrificed at 9 months old so that the protective effects of astaxanthin on the onset and progression of AD could be analyzed. In this model, we observed mild memory decline, accumulation of Ab42 in the hippocampus and PFC, a mild increase in pTau fraction, and microglial accumulation (an increase in Iba1 fraction) in the App NL-G-F mice, which is consistent with the previous studies (Saito et al, 2014;Masuda et al, 2016;Hashimoto et al, 2019). These deficits in memory functions may not be ascribed to confounding effects outside the brain such as deficits in visual acuity and locomotor activity in the App NL-G-F mice since a previous study reported that motor and visual capabilities of App NL-G-F and WT mice were comparable at 24 months old (Sakakibara et al, 2019).…”

“…The correlational analyses indicated that Ab42 fraction was positively correlated with pTau and Iba1 fraction, while memory functions (number of visits to the goal region) were negatively correlated with Ab and pTau fractions. These findings in this mouse AD model represent characteristics of human AD pathological findings and support the amyloid cascade theory of AD, in which accumulation of pathogenic Ab induces amyloid plaques, hyperphosphorylation of tau (tauopathy), and microglial activation (Hardy and Selkoe, 2002;Selkoe and Hardy, 2016;Sasaguri et al, 2017;Edwards, 2019;Hashimoto et al, 2019).…”

“…The deposits of Ab and the neurofibrillary tangles composed of hyperphosphorylated tau protein (pTau) are the neuropathological hallmarks of AD, and tauopathy is enhanced following Ab amyloidosis (Hardy and Selkoe, 2002;Perrin et al, 2009;Hashimoto et al, 2019). Therefore, we immunohistochemically investigated the effects of astaxanthin on the tauopathy in the control-fed WT (Figure 8A), control-fed App NL-G-F (Figure 8B), and astaxanthin-fed App NL-G-F mice ( Figure 8C).…”

“…Therefore, we hypothesized that astaxanthin's anti-oxidant effects may contribute to the prevention of the onset of cognitive deficits in AD through its effects on Ab accumulation, pTau, microglia, and PV-positive neurons. In the present study, the effects of astaxanthin intake on cognitive functions, histopathological progression of AD, and PV-positive neurons were investigated in a mouse model of AD with single App knock-in, which is free from side effects due to overexpression of amyloid precursor protein (APP) (Saito et al, 2014;Sasaguri et al, 2017;Hashimoto et al, 2019)…”

Detection of cerebral tauopathy in P301L mice using high-resolution large-field multifocal illumination fluorescence microscopy

“…Several tau mouse models that recapitulate pathological features of tauopathy have been developed with mutations in the MAPT gene, including P301S [13], P301L (rTg4510 under CaMKII [14], prion [15] and Thy1.2 [16] promotors), and hTau lines [17]. Whole brain highresolution tau imaging in these disease models provide insights for mechanistic and therapeutic studies [18,19].…”