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.

Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease

“…Evidence of vascular alterations and increased BBB permeability have been reported in T2DM patients [120,121] and in several experimental models of diabetes [122–125]. Multiple mechanisms may explain the link between T2DM and pathological changes in brain microvasculature, neurons and glial cells including increased levels of advanced glycation end-products (AGEs) and RAGE, vascular inflammation, oxidative stress, reduced insulin transport across the BBB, impaired insulin signaling, insulin resistance and endoplasmic reticulum stress [126,127].…”

Dopamine Adaptations as a Common Pathway for Neurocognitive Impairment in Diabetes and Obesity: A Neuropsychological Perspective

“…This poses a problem for interpreting the pathophysiology of the link between T2D and cognition because individuals with chronic T2D exhibit a number of pathologies associated with cognitive decline such as damage to the blood brain barrier (BBB), neuroinflammation (Banks et al, 2012; Steculorum et al, 2014), cerebral atrophy, and small vessel disease (Biessels and Reijmer, 2014; Akrivos et al, 2015; Ramos-Rodriguez et al, 2016; Stranahan et al, 2016). The co-occurrence of these pathologies that are secondary to diabetes has led to controversy over whether it is T2D (Biessels and Reagan, 2015) or complications arising from T2D that leads to cognitive decline (De Felice and Ferreira, 2014).…”

Mango leaf extract improves central pathology and cognitive impairment in a type 2 diabetes mouse model

“…The introduction of an RsaI site by the Leprdb mutation in the leptin receptor gene was detected by 126 PCR as previously described (26). As heterozygous (db/1) mice do not show specific phenotype at central or peripheral level (26,38), wild type and db/1 mice were included in the control group. Wild type, db/db and db/1 mice were generated from crosses between heterozygous db/1 mice and all mice were genotyped as previously described (13).…”

“…Western blot for phospho-tau and total-tau levels were performed in fresh tissue as previously described (38). Briefly, 50 mg of protein from cortex and hippocampus were loaded and separated on 10% acrylamide-bisacrylamide gels.…”

“…Inflammation was analyzed by microglia immunohistochemistry as previously described (38). Briefly, PFA-fixed 30 mm sections were immunostained with anti-IBA1 antibody (1:1000; Wako, Japan) followed by secondary goat anti-rabbit conjugated to Alexa 488 (1:1000; Invitrogen, The United States).…”