Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 56, Issue 1, Pages 1-23Publisher
IOS PRESS
DOI: 10.3233/JAD-160761
Keywords
Acetylcholinesterase; Alzheimer's disease; gliosis; high-fat diet; inflammation; memory; neurogenesis; rivastigmine; type 2 diabetes mellitus
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Funding
- JSPS KAKENHI [25115004]
- Novartis Pharma K.K.
- Iwadare Scholarship Foundation
- Grants-in-Aid for Scientific Research [25115004] Funding Source: KAKEN
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We previously reported that neuroinflammation contributes to the amnesia of A beta PPswe/PSEN1dE9 Alzheimer's disease model mice fed a high-fat diet to induce type-2 diabetes (T2DM-AD mice), but the underlying mechanism for the memory decline remained unclear. Recent studies have suggested that cholinergic modulation is involved in neuroinflammatory cellular reactions including neurogenesis and gliosis, and in memory improvement. In this study, we administered a broad-spectrum cholinesterase inhibitor, rivastigmine (2 mg/kg/day, s.c.), into T2DM-AD mice for 6 weeks, and evaluated their memory performance, neurogenesis, and neuroinflammatory reactions. By two hippocampal-dependent memory tests, the Morris water maze and contextual fear conditioning, rivastigmine improved the memory deterioration of the T2DM-AD mice (n=8, p < 0.01). The number of newborn neurons in the hippocampal dentate gyrus was 1138 +/- 324 (Ave +/- SEM) in wild-type littermates, 2573 +/- 442 in T2DM-AD-Vehicle, and 2165 +/- 300 in T2DM-AD-Rivastigmine mice, indicating that neurogenesis was accelerated in the two T2DM-AD groups (n=5, p < 0.05). The dendritic maturation of new neurons in T2DM-AD-Vehicle mice was severely abrogated, and rivastigmine treatment reversed this retarded maturation. In addition, the hippocampus of T2DM-AD-Vehicle mice showed increased proinflammatory cytokines IL-1 beta and TNF-alpha and gliosis, and rivastigmine treatment blocked these inflammatory reactions. Rivastigmine did not change the insulin abnormality or amyloid pathology in these mice. Thus, cholinergic modulation by rivastigmine treatment led to enhanced neurogenesis and the suppression of gliosis, which together ameliorated the memory decline in T2DM-AD model mice.
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