Dysfunction of striatal MeCP2 is associated with cognitive decline in a mouse model of Alzheimer’s disease

Lee S, Kim TK, Choi JE, Choi Y, You M, Ryu J, Chun YL, Ham S, Hyeon SJ, Ryu H, Kim H-S, and Im H-I.

Theranostics, 2022.

Scientists suggest MeCP2 as a novel therapeutic target for Alzheimer’s disease, with the potential to reverse or slow the progression of cognitive deficits.

Some studies suggest that the human striatum plays a role in the development of Alzheimer’s disease (AD), but the lack of telltale amyloid plaques in the brain region until the later stages of AD progression has puzzled scientists. Recently, however, evidence that the methyl-CpG binding protein 2 (MeCP2) in the striatum may regulate the risk of AD genes has provided a new avenue of research.

In this study, scientists used transgenic mouse models and postmortem brain samples from people with and without AD to analyze the functional role of striatal MeCP2 in AD-like cognitive dysfunction. Findings from the multiplatform approach, which included assessments of molecular, behavioral, and electrophysiological changes, revealed that MeCP2-mediated dysregulation of the striatal epigenome is associated with cognitive and neuronal abnormalities, and that these alterations begin in the very early stages of AD pathogenesis. Notably, the research team also demonstrated that regulating striatal function through the manipulation of MeCP2 improved cognitive dysfunction.

To examine neuronal activity induced by electrical stimulation, researchers placed brain slices of the striatum regions on Axion’s Maestro multielectrode array (MEA) platform. Findings from the MEA experiments showed that knock-down of MeCP2 expression rescued decreased striatal neuronal activity seen in amyloid-positive mouse models in the late stages of symptomatic cognitive dysfunction. Overall, the authors suggest that MeCP2 may be a novel therapeutic target with the potential to reverse or slow the progression of cognitive deficits observed early in the course of AD.