Reduction of NgR in perforant path decreases amyloid-β peptide production and ameliorates synaptic and cognitive deficits in APP/PS1 mice

Abstract

Background: Amyloid beta (Aβ) which is recognized as a main feature of Alzheimer's disease (AD) has been proposed to "spread" through anatomically and functionally connected brain regions. The entorhinal cortex and perforant path are the earliest affected brain regions in AD. The perforant path is the most vulnerable circuit in the cortex with respect to both aging and AD. Previous data show that the origins and terminations of the perforant path are susceptible to amyloid deposition at the younger age in AD. Nogo receptor (NgR) plays an essential role in limiting injury-induced axonal growth and experience-dependent plasticity in the adult brain. It has been suggested that NgR is involved in AD pathological features, but the results have been conflicting and the detailed mechanism needs further investigation. In this study, the effect of NgR in the perforant path on the pathological and functional phenotype of APP/PS1 transgenic mice was studied. Methods: To genetically manipulate NgR expression, adeno-associated virus (AAV) with short hairpin (shRNA) against NgR was injected into the perforant path of APP/PS1 transgenic mice, followed by an assessment of behavioral, synaptic plasticity and neuropathological phenotypes. NgR was overexpressed or knockdown in neuroblastoma N2a cells and APPswe/HEK293 cells to investigate the interaction between NgR and amyloid precursor protein (APP).

Long-Term Social Isolation-Induced Autophagy Inhibition and Cell Senescence Aggravate Cognitive Impairment in D(+)Galactose-Treated Male Mice

“…All the behavioral tests were performed by the EthoVision XT system (Noldus, Netherlands). The Morris water maze (MWM) was performed as described in our previous studies ( Jiang et al, 2020 ).…”

“…Passive avoidance learning was performed using a shuttle box, comprised of a brightly illuminated compartment connected to a dark compartment via a controllable door ( Jiang et al, 2020 ). The latency, frequency, and permanence time to (in) the dark compartment are the parameters for cognitive activity determination.…”

Nogo‑66 promotes β‑amyloid protein secretion via NgR/ROCK‑dependent BACE1 activation

“…The excess production of Aβ is considered the initiating factor of AD, which is generated from the hydrolysis of APP via BACE-1 and γ-secretase. NgR can cause parallel changes in sAPPα and Aβ, indicating that NgR blocks APP hydrolysis (26). In contrast to these findings, Zhou et al (24) reported that the increased interaction between NgR and APP reduced the surface expression of APP and favored the processing of APP via the BACE1 pathway.…”

Fasudil reduces β-amyloid levels and neuronal apoptosis in APP/PS1 transgenic mice via inhibition of the Nogo-A/NgR/RhoA signaling axis

“…Similarly, NgR plays an essential role in axonal and synaptic plasticity and may participate in the pathological process of AD by affecting the metabolism of amyloid precursor protein (Park and Strittmatter, 2008). Further study has demonstrated that NgR knockdown in the perforant path rescues cognitive deficits and synaptic function by decreasing the level of amyloid precursor protein and Aβ production (Jiang et al, 2020). p75NTR is a coreceptor for NgR, which mediates cellular apoptosis and survival and synapse weakening (Fahnestock and Shekari, 2019).…”