title: Long-term central pathology and cognitive impairment are exacerbated in a mixed model of Alzheimer's disease and type 2 diabetes.
abstract: Type 2 diabetes (T2D) is a well-characterized risk factor for Alzheimer's disease (AD), the most common cause of dementia. Since both, T2D and dementia are closely related to aging and they chronically coexist in elderly patients, it is of particular relevance to know whether long-term evolution of T2D and dementia interfere with each other years after the onset of the diseases. In order to elucidate this interaction, we have characterized a mixed model of T2D and AD, the APP/PS1xdb/db mouse, at 36 weeks of age, when both diseases have long coexisted and evolved. In aged APP/PS1xdb/db mice we observed dysfunctional metabolic control, when compared with diabetic mice alone, suggesting that AD may also contribute to T2D pathology in the long-term. Learning and memory were severely impaired in APP/PS1xdb/db mice, accompanied by reduced cortical size, neuronal branching simplification and reduction of dendritic spine density. Increased tau phosphorylation was also observed in old APP/PS1xdb/db mice. A shift in amyloid-β (Aβ) pathology was detected, and while insoluble Aβ was reduced, more toxic soluble species were favoured. Microglia burden was significantly increased in the proximity of senile plaques and an overall increase of spontaneous haemorrhages was also observed in APP/PS1xdb/db mice, suggesting a possible disruption of the blood brain barrier in the mixed model. It is therefore feasible that strict metabolic control may slow or delay central complications when T2D and dementia coexist in the long term.
authors.affiliation: Division of Physiology, School of Medicine, Institute of Biomolecules (INBIO), Universidad de Cadiz, Cadiz, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Infante-Garcia
authors.affiliation: Division of Physiology, School of Medicine, Institute of Biomolecules (INBIO), Universidad de Cadiz, Cadiz, Spain.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Ramos-Rodriguez
authors.affiliation: Division of Physiology, School of Medicine, Institute of Biomolecules (INBIO), Universidad de Cadiz, Cadiz, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Galindo-Gonzalez
authors.affiliation: Division of Physiology, School of Medicine, Institute of Biomolecules (INBIO), Universidad de Cadiz, Cadiz, Spain. Electronic address: monica.garcia@uca.es.
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia-Alloza
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000473:pathology*; D015897:Comorbidity; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology* / Q000523:psychology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D004195:Disease Models, Animal; D051379:Mice; D008815:Mice, Inbred Strains; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins
keywords: Alzheimer’s disease; Amyloid-beta; Haemorrhage; Tau; Type 2 diabetes