Aβ1-42 Accumulation Accompanies Changed Expression of Ly6/uPAR Proteins, Dysregulation of the Cholinergic System, and Degeneration of Astrocytes in the Cerebellum of Mouse Model of Early Alzheimer Disease

Alzheimer disease (AD) is a widespread neurodegenerative disease characterized by the accumulation of oligomeric toxic forms of beta-amyloid (A beta 1-42) and dysfunction of the cholinergic system in the different brain regions. However, the exact mechanisms of AD pathogenesis and the role of the nicotinic acetylcholine receptors (nAChRs) in the disease progression remain unclear. Here, we revealed a decreased expression of a number of the Ly6/uPAR proteins targeting nAChRs in the cerebellum of 2xTg-AD mice (model of early AD) in comparison with non-transgenic mice both at mRNA and protein levels. We showed that co-localization of one of them, - neuromodulator Lynx1, with alpha 7-nAChR was diminished in the vicinity of cerebellar astrocytes of 2xTg-AD mice, while A beta 1-42 co-localization with this receptor present was increased. Moreover, the expression of anti-inflammatory transcription factor KLF4 regulating transcription of the Ly6/uPAR genes was decreased in the cerebellum of 2xTg-AD mice, while expression of inflammatory cytokine TNF-alpha was increased. Based on these data together with observed astrocyte degeneration in the cerebellum of 2xTg-AD mice, we suggest the mechanism by which expression of the Ly6/uPAR proteins upon A beta pathology results in dysregulation of the cholinergic system and particularly of alpha 7-nAChR function in the cerebellum. This leads to enhanced neuroinflammation and cerebellar astrocyte degeneration.

Automated summary

Alzheimer's disease is a neurodegenerative disease characterized by the accumulation of toxic forms of beta-amyloid and dysfunction of the cholinergic system. This study found decreased expression of Ly6/uPAR proteins targeting nicotinic acetylcholine receptors (nAChRs) in the cerebellum of AD mice, as well as diminished co-localization of the neuromodulator Lynx1 with alpha 7-nAChR and increased co-localization of A beta 1-42 with this receptor. Additionally, the decreased expression of the anti-inflammatory transcription factor KLF4 and increased expression of the inflammatory cytokine TNF-alpha were observed. These findings suggest that the dysregulation of Ly6/uPAR proteins results in cholinergic system dysfunction and neuroinflammation in the cerebellum.