Diet‐induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease

Abstract

Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.

High‐fat diet protects the blood–brain barrier in an Alzheimer's disease mouse model

“…Some experimental studies support the notion that HFD‐induced obesity exacerbates cerebral pathological alterations and the accompanying cognitive deficit in APP transgenic mice (Ho et al, 2004). In wild‐type mice, some studies suggest that HFD impairs cognition (Winocur & Greenwood, 2005) while other claim for no effect (Kesby et al, 2015) or even improvement of memory (Coscina et al, 1986) and protection from age‐related cognitive decline (Scheibye‐Knudsen et al, 2014).…”

“…The impact of HFD on memory and cognition is also controversial and depends on the composition of the fat and the time of exposure to HFD. Some experimental studies support the notion that HFD‐induced obesity exacerbates cerebral pathological alterations and the accompanying cognitive deficit in APP transgenic mice (Ho et al, 2004) while other claim for no effect (Kesby et al, 2015) or even improvement of memory in mice (Coscina, Yehuda, Dixon, Kish, & Leprohon‐Greenwood, 1986). …”

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

“…Alzheimer's disease is the most common form of dementia, characterised by loss of recent memory as one of the first symptoms and a progressive decline in all cognitive skills later on in the disease [3,26]. Considerable evidence suggests that insulin resistance and obesity may directly contribute to the pathogenesis of Alzheimer's disease [27][28][29][30][31]. However, not much emphasis has been put on the role of Alzheimer's disease in obesity and type 2 diabetes development, as characterised by insulin resistance.…”

“…We found that under HFD feeding conditions, basal S6 phosphorylation was significantly higher in brains from PSEN1 and APP/PSEN1 mice and was as high as the insulin-stimulated S6 phosphorylation observed in wildtype mice, consistent with the insulin resistance observed in Alzheimer's disease mice. Since a decrease in insulinstimulated Akt/PKB phosphorylation was observed in other mouse models of Alzheimer's disease in specific regions of brain or peripheral tissues [16,28], we examined Akt/PKB phosphorylation from whole-brain lysates, finding, as expected from their impaired glucose tolerance, that insulin-stimulated Akt/PKB phosphorylation was decreased in PSEN1 and APP/PSEN1 mice under chow as well as HFD feeding conditions. In addition, insulin-stimulated phosphorylation of ERK1 and -2 was downregulated in PSEN1 and APP/PSEN1 mice in comparison to wild-type controls, both on chow and HFD.…”

Ketone Bodies as a Therapeutic for Alzheimer's Disease

“…3B). 44 At first, this result may seem at odds with earlier studies that attributed high-fat diets to increased A␤ loads 46,47 ; however, in these earlier studies, fat was added to the diet without substantial decrease in carbohydrate content. It is unlikely these animals produced KB.…”