Immunohistochemical relationships of huntingtin-associated protein 1 with choline acetyltransferase in the forebrain cholinergic nuclei of adult mice.

Huntingtin-associated protein 1 (HAP1) is a core component of the stigmoid body (STB) and a neuroprotective interactor with the causative agents of several neurodegenerative diseases (NDs). The cholinergic system is often affected by NDs. Our previous studies suggest that cholinergic brainstem/spinal cord motoneurons are more vulnerable to neurodegeneration due to a lack of STB/HAP1 protectivity. The forebrain cholinergic nuclei are also major neurodegenerative/psychotic targets; however, the relationships of HAP1 with choline acetyltransferase (ChAT) have yet to be determined there. This study used western blotting and immunohistochemistry to evaluate the comparative distribution of HAP1 with ChAT and their immunohistochemical relationships in the adult mouse forebrain cholinergic nuclei. The results showed that HAP1-immunoreactive (ir) neurons were highly distributed in the basal forebrain cholinergic nuclei, including medial septal nucleus (MS), nucleus of vertical limb of the diagonal band of Broca (VDB), nucleus of horizontal limb of the diagonal band of Broca (HDB), and substantia innominata basal part (SIB). HAP1-ir neurons were sporadically scattered in the striatum. The significantly highest co-expression ratio of HAP1 with ChAT was observed in MS and VDB. In contrast, the ChAT-ir neurons never contained HAP1 in the caudate putamen of the striatum. These suggest that, due to having putative HAP1 protectivity, the cholinergic neurons in MS and VDB that are mainly projected to the hippocampal/parahippocampal regions might be protected to regulate social memory formation, emotion, and other psychological functions. Consequently, the lack of HAP1 protectivity might make cholinergic neurons in the striatum more prone to neurodegeneration in certain NDs.