Prediabetes-induced vascular alterations exacerbate central pathology in APPswe/PS1dE9 mice

Augmented Insulin and Leptin Resistance of High Fat Diet-Fed APPswe/PS1dE9 Transgenic Mice Exacerbate Obesity and Glycemic Dysregulation

“…No difference in the weight gain and glucose level was observed between wild type (WT) and APP/PS1 transgenic (AD) mice after 23- or 32-week HFD treatment in previous studies [3,23]. Our study has suggested that the duration of HFD treatment and age-related AD pathology of AD mice determine their individual impact on body weight gain and hyperglycemia [4].…”

“…Although the etiology of sporadic AD is largely unknown, impaired metabolic parameters including glycemic dysregulation and obesity are correlated with the development of AD-related pathology [2]. Hyperglycemia and obesity induced by a high fat diet (HFD) have been shown to exacerbate the amyloid pathology and cognitive impairment of AD transgenic mice and human [3,4,5]. Conversely, AD-related pathology leads to augmented obesity and glycemic dysregulation [4,6].…”

Impaired cognition and cerebral glucose regulation are associated with astrocyte activation in the parenchyma of metabolically stressed APPswe/PS1dE9 mice

“…Accumulating evidence indicates that HFD or diabetic syndrome hinders the functioning of the cerebrovascular perfusion system in AD mouse models through microhemorrhage or inflammation (Ramos-Rodriguez et al, 2014;Takeda et al, 2010). Our observation of microvascular IL-6 upregulation and parenchyma astrocyte activation suggests that HFSTZ treatment alters the cerebral microenvironment, promoting plaque formation and thus contributing to impaired nest construction and MRglu by enhancing the production and reducing the clearance of Ab in multiple brain regions.…”

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

“…However, we can not obviate that altered insulin levels "per se" might, at least in part, be responsible for observed central pathology. In this sense, it has been described that prediabetic hyperinsulinemic mice, with normoglycemia, also present central alterations after long-term high fat diet (Ramos-Rodriguez et al, 2014) whereas APP/PS1xdb/db mice show an overall worsened central phenotype.…”

“…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).…”