Cell Biology of Bioactive Peptide Secretion

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

Type 2 diabetes (T2D) is recognized as a major risk factor for Alzheimer?s Disease (AD) and AD patients are at increased risk for the development of T2D. Although the underyling mechanisms responsible for this bidirectional association are unknown, it is clear that the thiazolidinediones (TZDs) used to treat T2D can ameliorate some of the deficits associated with AD. Our hypothesis is that alterations in the function of genes that play essential roles in the biosynthesis and secretion of peptide hormones contribute to the T2D/AD association. Peptidylglycine ?-amidating monooxygenase (PAM), which plays a well conserved role in secretory granule maturation and secretion, is a risk factor for T2D and hypertension. Kalirin (KALRN), a multi-domain Rho GDP/GTP exchange factor (GEF) first identified through its interaction with PAM, is a risk factor for AD, early onset coronary artery disease, schizophrenia, and attention deficit hyperactivity disorder. Our previous studies demonstrated that aging mice with a single copy of Pam exhibit decreased glucose tolerance and increased adiposity, and that mice lacking Kalrn exhibit cardiovascular and bone phenotypes along with impaired ?-cell, somatotrope and lactotrope secretion. We previously showed that Kalirin7 (Kal7), the major adult isoform, is essential for normal neuronal dendritic spine formation and electrophysiological function. Kal7 levels are low in postmortem hippocampal tissue from AD patients vs. controls, and expression of exogenous Kal7 elicits a long-lasting rescue of synaptic plasticity and memory in mouse models of AD. We will use our mouse models of Kalrn deficiency and our detailed knowledge of this complex set of proteins to evaluate KALRN and the regulated secretory pathway as a target for the treatment of AD and AD related dementia. Hypothesis 1: Kalrn deficits contribute to the metabolic, learning and memory deficiencies observed in AD mouse models. The 3xTg-AD model mice, which express mutant amyloid precursor protein (APP-Swedish), mutant presenilin 1 (Psen1; M146V knockin) and mutant Tau (P301L) proteins, will be bred to Kalrn-/- mice. If Kalrn plays a role in the pathways affected by these AD mutations, as demonstrated by morphological and biochemical analyses, cognitive function will be significantly more impaired in AD mice with a single copy of Kalrn than in AD mice with two copies of Kalrn. Hypothesis 2: Kalrn deficits contribute to deficiencies that occur in vascular dementia. The responses of wildtype and Kalrn+/- mice (male and female) to the multiple infarct embolic stroke model will be compared. Long term cognitive function and metabolic parameters will be assessed.