Reduction in hippocampal cholinergic neurostimulating peptide enhances memory impairment in App NL‐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 ( App NL‐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 App NL‐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 App NL‐G‐F KI/HCNP‐pp cKO mice. DISCUSSION Cholinergic dysfunction in HCNP‐pp cKO mice exacerbates cognitive dysfunction in App NL‐G‐F KI mice. The obtained mouse models are expected to be used to investigate cholinergic dysfunction and amyloid pathogenesis in AD.