Simvastatin rescues memory and granule cell maturation through the Wnt/β-catenin signaling pathway in a mouse model of Alzheimer’s disease

• Published in: Cell death & disease Vol. 13; no. 4; p. 325
• Main Authors: Tong, Xin-Kang, Royea, Jessika, Hamel, Edith
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.04.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/51; 14/19; 631/378/368/2431; 64; 64/60; 692/699/375/132/1283; 82/51; 82/80; Age; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Animals; Antibodies; beta Catenin - metabolism; Biochemistry; Biomedical and Life Sciences; Calbindin; Cell Biology; Cell Culture; Cognitive ability; Dentate gyrus; Disease Models, Animal; Dkk1 protein; Doublecortin protein; Granule cells; Hippocampus; Hippocampus - metabolism; Immediate-early proteins; Immunology; Ki-67 Antigen - metabolism; Life Sciences; Memory; Mice; Neurodegenerative diseases; Neurogenesis; Neurogenesis - physiology; Neurons - metabolism; Signal transduction; Simvastatin; Simvastatin - pharmacology; Simvastatin - therapeutic use; Wnt protein; Wnt Signaling Pathway; β-Catenin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-04784-y

We previously showed that simvastatin (SV) restored memory in a mouse model of Alzheimer disease (AD) concomitantly with normalization in protein levels of memory-related immediate early genes in hippocampal CA1 neurons. Here, we investigated age-related changes in the hippocampal memory pathway, and whether the beneficial effects of SV could be related to enhanced neurogenesis and signaling in the Wnt/β-catenin pathway. APP mice and wild-type (WT) littermate controls showed comparable number of proliferating (Ki67-positive nuclei) and immature (doublecortin (DCX)-positive) granule cells in the dentate gyrus until 3 months of age. At 4 months, Ki67 or DCX positive cells decreased sharply and remained less numerous until the endpoint (6 months) in both SV-treated and untreated APP mice. In 6 month-old APP mice, dendritic extensions of DCX immature neurons in the molecular layer were shorter, a deficit fully normalized by SV. Similarly, whereas mature granule cells (calbindin-immunopositive) were decreased in APP mice and not restored by SV, their dendritic arborizations were normalized to control levels by SV treatment. SV increased Prox1 protein levels (↑67.7%, p  < 0.01), a Wnt/β-catenin signaling target, while significantly decreasing (↓61.2%, p  < 0.05) the upregulated levels of the β-catenin-dependent Wnt pathway inhibitor DKK1 seen in APP mice. In APP mice, SV benefits were recapitulated by treatment with the Wnt/β-catenin specific agonist WAY-262611, whereas they were fully abolished in mice that received the Wnt/β-catenin pathway inhibitor XAV939 during the last month of SV treatment. Our results indicate that activation of the Wnt-β-catenin pathway through downregulation of DKK1 underlies SV neuronal and cognitive benefits.