title: Increased Spontaneous Central Bleeding and Cognition Impairment in APP/PS1 Mice with Poorly Controlled Diabetes Mellitus.
abstract: Alzheimer's disease (AD) and vascular dementia (VaD) are the most common causes of dementia, and borderlines are blurred in many cases. Aging remains the main risk factor to suffer dementia; however, epidemiological studies reveal that diabetes may also predispose to suffer AD. In order to further study this relationship, we have induced hypoinsulinemic diabetes to APPswe/PS1dE9 (APP/PS1) mice, a classical model of AD. APP/PS1 mice received streptozotocin (STZ) ip at 18 weeks of age, when AD pathology is not yet established in this animal model. Cognition was evaluated at 26 weeks of age in the Morris water maze and the new object discrimination tests. We observed that STZ-induced episodic and working memory impairment was significantly worsened in APP/PS1 mice. Postmortem assessment included brain atrophy, amyloid-beta and tau pathology, spontaneous bleeding, and increased central inflammation. Interestingly, in APP/PS1-STZ diabetic mice, we detected a shift in Aβ soluble/insoluble levels, towards more toxic soluble species. Phospho-tau levels were also increased in APP/PS1-STZ mice, accompanied by an exacerbated inflammatory process, both in the close proximity to senile plaque (SP) and in SP-free areas. The presence of hemorrhages was significantly higher in APP/PS1-STZ mice, and although pericytes and endothelium were only partially affected, it remains possible that blood-brain barrier alterations underlie observed pathological features. Our data support the implication of the diabetic process in AD and VaD, and it is feasible that improving metabolic control could delay observed central pathology.
authors.affiliation: Division of Physiology, School of Medicine, Instituto de Biomoleculas (INBIO), Universidad de Cadiz, Plaza Fragela 9, 4 piso, 410, Cadiz, 11003, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Ramos-Rodriguez
authors.affiliation: Division of Physiology, School of Medicine, Instituto de Biomoleculas (INBIO), Universidad de Cadiz, Plaza Fragela 9, 4 piso, 410, Cadiz, 11003, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Infante-Garcia
authors.affiliation: Division of Physiology, School of Medicine, Instituto de Biomoleculas (INBIO), Universidad de Cadiz, Plaza Fragela 9, 4 piso, 410, Cadiz, 11003, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Galindo-Gonzalez
authors.affiliation: Division of Physiology, School of Medicine, Instituto de Biomoleculas (INBIO), Universidad de Cadiz, Plaza Fragela 9, 4 piso, 410, Cadiz, 11003, Spain.
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Garcia-Molina
authors.affiliation: Department of Radiology and Pediatrics, Universidad de Cadiz, Cadiz, 11003, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lechuga-Sancho
authors.affiliation: Division of Physiology, School of Medicine, Instituto de Biomoleculas (INBIO), Universidad de Cadiz, Plaza Fragela 9, 4 piso, 410, Cadiz, 11003, Spain. monica.garcia@uca.es.
authors.forename: Mónica
authors.initials: M
authors.lastname: Garcia-Alloza
mesh_terms: D000682:Amyloid / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001284:Atrophy; D001921:Brain / Q000098:blood supply / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D003072:Cognition Disorders / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D007339:Insulysin / Q000378:metabolism; D008568:Memory; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity; D015260:Neprilysin / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism*; D013311:Streptozocin; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D016875:tau Proteins; D013311:Streptozocin; D015260:Neprilysin; D007339:Insulysin
keywords: Alzheimer’s disease; Amyloid-beta; Diabetes; Hemorrhage; Streptozotocin; Vascular dementia