Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Reduction in hippocampal cholinergic neurostimulating peptide enhances memory impairment in AppNL-G-F KI mice.
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Tsuda Yo, Madokoro Yuta, Suzuki Kengo, Ooba Takuya, Sato Toyohiro, Uchida Yuto, Nagai-Arakawa Itsumi, Saito Takashi, Hara Hideaki, Hida Hideki, Matsukawa Noriyuki
Аннотация
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.
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.