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

Abstract

SPECIFIC AIMSInsulin 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). To clarify how NIDDM may influence Alzheimer’s disease (AD) neuropathology, we explore the role of experimental NIDDM-like insulin resistance in the Tg2576 mouse model, which develops AD type neuropathology.PRINCIPAL FINDINGS1. We found that a diet that induces insulin resistance promoted amyloidogenic β-amyloid (Aβ) Aβ1-40 and Aβ1-42 peptide generation (Fig. 1⤻ A) and amyloid plaque burden (Fig. 1B⤻ ) in the brain of Tg2576 mice that corresponded with increased γ-secretase activities and decreased insulin-degrading enzyme (IDE) activity. Moreover, increased Aβ production coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task (see online article). Figure 1.Diet-induced insulin resistance-mediated promotion of AD-type amyloid burden is a...