Evidence for a protective effect of the loss of 4-containing nicotinic acetylcholine receptors on A-related neuropathology in Tg2576 mice

Introduction: Loss of cholinergic neurons as well as a4 ss 2* (*=containing) nicotinic acetylcholine receptors (nAChRs) is a prominent feature of Alzheimer's disease (AD). Specifically, amyloid ss (A ss), the principal pathogenic factor of AD, is a high affinity ligand for nAChRs. Yet, the pathophysiological role of nAChRs in AD is not well established. Methods: In the present study, we have investigated the effects of the loss of a4* nAChRs on the histological alterations of the Tg2576 mouse model of AD (APPswe) crossing hemizygous APPswe mice with mice carrying the genetic inactivation of a4 nAChR subunit (a4KO). Results: A global decrease in A ss plaque load was observed in the forebrain of APPswe/a4KO mice in comparison with APPswe mice, that was particularly marked in neocortex of 15month-old mice. At the same age, several alterations in synaptophysin immunoreactivity were observed in cortico-hippocampal regions of APPswe mice that were partially counteracted by a4KO. The analysis of the immunoreactivity of specific astroglia (glial fibrillary acidic protein, GFAP) and microglia (ionized calcium-binding adapter molecule, Iba1) markers showed an increase in the number as well as in the area occupied by these cells in APPswe mice that were partially counteracted by a4KO. Conclusion: Overall, the present histological study points to a detrimental role of a4* nAChRs that may be specific for A ss-related neuropathology.