Association Between CDH1 Downregulation and Lymphocyte Cell-Cycle Dysfunction in Alzheimer's Disease and Mild Cognitive Impairment.

Abstract

Alzheimer’s disease (AD) is characterized by the intracellular accumulation of amyloid-β and tau pathology, which disrupt multiple cellular regulatory pathways, including those involved in cell cycle control. Dysregulation of the anaphase-promoting complex/cyclosome (APC/C), particularly through altered expression of its coactivator CDH1, has been implicated in neuronal dysfunction in AD. Beyond the central nervous system, increasing evidence suggests that peripheral immune cells also exhibit functional alterations associated with the disease. In this study, we recruited patients with mild cognitive impairment (MCI) and AD, along with non-demented controls. We isolated T lymphocytes to assess mitogen-induced lymphocyte proliferation and associated molecular changes. We report that lymphocytes from MCI and AD patients show a reduced proliferative response compared to controls, accompanied by decreased CDH1 mRNA expression and altered expression of APC/C-related genes. These changes were associated with markers of oxidative stress and cellular stress pathways. Together, our findings identify an association between reduced CDH1 expression and impaired lymphocyte proliferation in AD and MCI, supporting the relevance of peripheral immune cells as candidates for systemic markers of disease-related cellular dysfunction.