Reduction in hippocampal cholinergic neurostimulating peptide enhances memory impairment in AppNL-G-F KI mice.

INTRODUCTION

Whether cholinergic activity in the septohippocampal network affects cognitive dysfunction via hippocampal cholinergic neurostimulating peptide (HCNP) in Alzheimer's pathogenesis remains unclear.

METHODS

An Alzheimer's pathogenesis by mutation in amyloid-beta precursor protein gene (AppNL-G-F) knock-in (KI) and HCNP precursor protein conditional knockout (HCNP-pp cKO) mouse model was generated, exhibiting both cholinergic dysfunction and amyloid pathogenesis. Theta power-related cholinergic function and long-term potentiation (LTP) were evaluated in AppNL-G-F KI/HCNP-pp cKO mice. Molecules associated with the cholinergic/glutamatergic neurons, amyloid beta (Aβ), and inflammation were examined.

RESULTS

Reduced HCNP levels enhanced cognitive impairment, inhibiting theta power and LTP, although without accompanying pathological changes or inflammation. Decreased N-methyl-D-aspartate receptor subunit 2A (NR2A), choline acetyltransferase (ChAT), and Vesicular acetylcholine transporter (VAChT) levels were observed in the hippocampus and ChAT in the medial septal nucleus (MSN) of AppNL-G-F KI/HCNP-pp cKO mice.

DISCUSSION: Cholinergic dysfunction in HCNP-pp cKO mice exacerbates cognitive dysfunction in AppNL-G-F KI mice. The obtained mouse models are expected to be used to investigate cholinergic dysfunction and amyloid pathogenesis in AD.