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Type 2 diabetes (T2D) is a major risk factor for late-onset Alzheimer's disease (AD). A variety of metabolic changes related to T2D (e.g. hyperinsulinemia, hyperglycemia, and elevated branched-chain amino acids) have been proposed as mechanistic links, but the basis for this association remains unknown. Retromer-dependent trafficking is implicated in the pathogenesis of AD, and two key retromer proteins, VPS35 and VPS26, are deficient in the hippocampal formation of AD patients. We characterized VPS35 levels in five different mouse models of T2D/obesity to identify specific metabolic factors that could affect retromer levels in the brain. Mouse models in which hyperleucinemia was present displayed hippocampus-selective retromer deficiency. Wild-type lean mice fed a high leucine diet also developed hippocampal-selective retromer deficiency, and neuronal-like cells grown in high ambient leucine had reduced retromer complex proteins. Our results suggest that hyperleucinemia may account, in part, for the association of insulin resistance/T2D with AD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Taste consumption activates the extracellular responsive kinases 1-2 (ERK1-2) and the transcription factor Elk-1 in the insular cortex (IC) of the behaving rat. ERKs activation, an obligatory step for the encoding of long- but not short-term memory, was shown to be regulated by multiple neurotransmitter systems in the IC. Here I show, by the use of local microinfusions of pharmacological agents into the IC of the behaving rat, that a set of similar systems is required for the taste-induced activation of Elk-1. N-Methyl-D-aspartate (NMDA), glutamate metabotropic (mGlu), ionotropic AMPA/kainate (AMPA), muscarinic, and dopaminergic receptors, which all contribute to the acquisition of taste memory, are also responsible for Elk-1 activation. However, blockade of the beta-adrenergic transmission does not affect Elk-1 activation. I also show that the basal level of Elk-1 activation in cortex is mainly maintained by GABAergic transmission. Thus, the formation of taste memory triggers the activation of Elk-1 in the IC of the behaving rat via selected neurotransmitter and neuromodulatory systems.