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Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer’s knock-in mouse phenotypes

ABSTRACT: Clinically, patients with diabetes have a higher risk of suffering from Alzheimer's disease (AD), with increased severity of cognitive decline upon disease onset. Several studies have reported on the metabolic impact of chronic hyperglycemia using various mouse models of AD, with varying results and behavioral outcomes. Furthermore, the underlying cellular mechanisms driving any observable increases in cognitive impairments remain unclear. In this study, we induced either Type-1 (streptozotocin, STZ) or Type-2 (chronic high-fat diet, HFD) diabetes on either wild type or a double knock-in AD mouse model. We found that there was no observable difference in behavioral defect between AD and AD mice with STZ-induced diabetes. However, AD mice on a chronic high-fat diet displayed increased impairments in memory and learning. Histological and transcriptomic analysis of these mice revealed an increase in glial-mediated synapse due to an altered metabolic state of microglia.

ORGANISM(S): Mus musculus

PROVIDER: GSE262426 | GEO | 2025/11/01

REPOSITORIES: GEO

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Project description:Thiazolidinediones (TZDs) are agonists at peroxisome proliferator-activated gamma-type (PPAR-y) receptors and are used clinically for the treatment of type 2 diabetes where they have been shown to reestablish insulin sensitivity, improve lipids profile, and reduce inflammation. Recent work also suggests that TZDs may be beneficial in Alzheimer's disease (AD), ameliorating cognitive decline early in the disease process. However, there have been only a few studies identifying mechanisms through which cognitive benefits may be exerted. Starting at 10 months of age, the triple transgenic mouse model of AD (3xTg-AD) with accelerated amyloid-B (AB) deposition and tau pathology was treated with the TZD pioglitazone (PIO- Actos) at 18 mg/Kg body weight/day. After four months, PIO-treated animals showed multiple beneficial effects, including improved learning on the active avoidance task, reduced serum cholesterol, decreased hippocampal AB deposits, and enhanced short- and long-term plasticity. Baseline electrophysiological membrane properties and blood glucose levels were unchanged by PIO treatment. Gene microarray analyses of hippocampal tissue identified predicted transcriptional responses following TZD treatment as well as potentially novel targets of TZDs, including facilitation of estrogenic processes, and decreases in glutamatergic and ketone metabolic/ cholesterol dependent processes. Taken together, these results confirm prior animal studies showing that TZDs can ameliorate cognitive deficits associated with AD-related pathology, but also extend these findings by pointing to novel molecular targets in the brain. Keywords : Hippocampus; LTP; Microarray analysis; Avoidance learning; Aging; PPAR; Synaptic hyperpolarization; T2DM We used the 3xTg-AD mouse model of Alzheimer's disease and monitored the effects of pioglitazone (PIO-Actos a TZD) on behavioral, electrophysiological, and molecular variables. Emphasis was placed on identifying hippocampal PIO-sensitive genes that were also associated with learning and memory processes. Starting at 10 months of age, female mice were treated for approximately 14 weeks with either a control diet or a PIO-containing diet. PIO was incorporated into the diet to yield a final dose of approximately 18 mg/kg body weight/day.

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Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer’s knock-in mouse phenotypes

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