ArticleActa neuropathologica communications2014
Obesity and diabetes cause cognitive dysfunction in the absence of accelerated β-amyloid deposition in a novel murine model of mixed or vascular dementia.
Article in Acta neuropathologica communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 84 citations in OpenAlex.
- Article
- Interactions between daily sleep-wake rhythms, γ-secretase, and amyloid-β peptide pathology point to complex underlying relationships.Biochimica et biophysica acta. Molecular basis of disease · 2025Article
- Circulating non-esterified fatty acids, risk of dementia and cognitive decline: The cardiovascular health study and multi-ethnic study of atherosclerosis.Neurobiology of aging · 2025Article
- Risk Factors, Pathological Changes, and Potential Treatment of Diabetes-Associated Cognitive Dysfunction.Journal of diabetes · 2025Review
- Relationship between Alzheimer's Disease and Type 2 Diabetes: Critical Review On Cellular and Molecular Common Pathogenic Mechanisms.Current Alzheimer research · 2025Review
- Alzheimer's Disease, Obesity, and Type 2 Diabetes: Focus on Common Neuroglial Dysfunctions (Critical Review and New Data on Human Brain and Models).Brain sciences · 2024Review
- Longitudinal Genome-Wide Association Study of Cognitive Impairment after Subarachnoid Hemorrhage.Biomedicines · 2024Article
- Investigating metabolic dysregulation in serum of triple transgenic Alzheimer's disease male mice: implications for pathogenesis and potential biomarkers.Amino acids · 2024Article
- Incidence of microvascular dysfunction is increased in hyperlipidemic mice, reducing cerebral blood flow and impairing remote memory.Frontiers in endocrinology · 2024Article
- Exposure to Lead in Drinking Water Causes Cognitive Impairment via an Alzheimer's Disease Gene-Dependent Mechanism in Adult Mice.Journal of Alzheimer's disease : JAD · 2024Article
- Article
- Reduced endothelial caveolin-1 underlies deficits in brain insulin signalling in type 2 diabetes.Brain : a journal of neurology · 2023Article
- Exploration and Clinical Verification of the Blood Co-Expression Genes of Type 2 Diabetes Mellitus and Mild Cognitive Dysfunction in the Elderly.Biomedicines · 2023Article
- Impact of non-neuronal cells in Alzheimer's disease from a single-nucleus profiling perspective.Frontiers in cellular neuroscience · 2023Review
- Neuroprotection from protein misfolding in cerebral hypoperfusion concurrent with metabolic syndrome. A translational perspective.Frontiers in neuroscience · 2023Review
- Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes.Fluids and barriers of the CNS · 2022Article
- Rodent Models of Post-Stroke Dementia.International journal of molecular sciences · 2022Review
- Article
- Endoplasmic reticulum stress contributes to the decline in doublecortin expression in the immature neurons of mice with long-term obesity.Scientific reports · 2022Article
- Nonobese Male Patients with Alzheimer's Disease Are Vulnerable to Decrease in Plasma Leptin.Journal of Alzheimer's disease : JAD · 2022Article
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Authors and funding
19 authors at 1 institution in 1 country.
Funding
Abstract
Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer's disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APPΔNL/ΔNLx PS1P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of β-amyloid (Aβ)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Aβ deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Aβ was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Aβ-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APPΔNLx PS1P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Aβ deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics.
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