Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice

Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease

“…Out of the resulting offsprings, male APP/PS1 +/-db/db +/− and female APP/PS1 -/-db/db +/− were selected to generate the 6 possible groups: APP/PS1 -/-db/db +/+ , APP/PS1 -/-db/db +/-, APP/PS1 -/-db/db -/-, APP/PS1 +/-db/db +/+ , APP/PS1 +/-db/db +/− and APP/PS1 -/-db/db -/− . As previously described, heterozygous db/db mice do not present specific metabolic or central phenotype (Ramos-Rodriguez et al, 2013c) and therefore animals were grouped as follows: Control (APP/PS1 -/-db/db +/+ , APP/PS1 -/-db/db +/− mice), APP/PS1 (APP/PS1 +/-db/db +/+ and APP/PS1 +/-db/db +/− mice), db/db mice (APP/PS1 -/-db/db -/− ) and APP/PS1xdb/db (APP/PS1 +/-db/db -/− mice). In order to fully characterize the model, animals were aged up to 4, 14 and 26 weeks of age.…”

“…Blood from the tail was preserved into capillary tubes precoated with potassium-EDTA (Sarstedt, Nümbrecht, Germany) for insulin determinations and homeostasis model of assessment-insulin resistance (HOMA-IR) was used to analyze insulin resistance [(HOMA-IR = fasting serum insulin (U/mL) × fasting serum glucose (mg/dL)/405)], as previously described (Saraswathi et al, 2013). Lipid profile was completed by cholesterol and triglycerides levels determinations as previously described (Ramos-Rodriguez et al, 2013c). Effect on cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides levels was also determined in groups under study.…”

“…On the other hand, hyperinsulinemia, as present at early stages of T2D, may alter A␤ levels by indirect mechanisms, like exacerbation of inflammatory responses that interact with A␤ processing and deposition (for review see (Bosco et al, 2011;Garcia-Alloza, 2014)). Other AD neuropathological features, such as tau phosphorylation, are also severely affected when insulin levels are altered, both in hyper and hypoinsulinemic situations (Clodfelder-Miller et al, 2006;Kim et al, 2009;Ramos-Rodriguez et al, 2013b;Ramos-Rodriguez et al, 2014). Insulin and A␤ are degraded by the same two proteases, neprilysin (NEP) and insulin degrading enzyme (IDE), and thus, direct substrate competition may alter regular proteolysis of both insulin and A␤ (Farris et al, 2003;Liu et al, 2010), and possibly influence the pathogenesis of AD and T2D (Gotz et al, 2009).…”

Metabolic tinkering by the gut microbiome

“…87 Furthermore, dietary administration of butyrate was shown to improve insulin sensitivity and enhance mitochondrial function in peripheral tissue. 119 The brain is not entirely protected from metabolic disturbances and many of the molecular mediators of T2D, including insulin and leptin, have been associated with dementia [120][121][122] (reviewed in refs. 123,124).…”

Hyperphosphorylation of Tau Protein in Hippocampus of Central Insulin-Resistant Rats is Associated with Cognitive Impairment

“…Multiple studies have demonstrated that tau protein is the major protein component of NFTs in the brain of AD patients, and abnormally hyperphosphorylation of tau protein plays a key role in NFT formation [6]. Accumulating evidence indicates that insulin resistance (IR) is one of the risk factors for AD, and abnormal insulin levels in the brain may be an important cause of AD [7,8,9,10,11]. Streptozotocin (STZ) is a glucosamine-nitrosourea compound that decreases both insulin receptor autophosphorylation in neurons and endogenous tyrosine kinases activation [12,13], which may increase the activity of phosphotyrosine phosphatase to inhibit insulin signaling [14].…”