Impact of aging, sex, vitamin D deficiency and high cholesterol on beta-amyloid peptide accumulation in brains of guinea pigs

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A major puzzle with aging is the loss of brain function. ß-Amyloid peptides of 40 and 42 amino acid lengths (Aß40 and Aß42) are pathologic cleavage products that are being formed increasingly from the amyloid precursor protein (APP) with aging. Other modulating factors may be sex, vitamin D-deficiency and high cholesterol. The synthesis of Aß from APP occurs via sequential cleavage by the ß- and ?- secretases. The Aß monomers progress to oligomers then aggregate to plaques. Removal of Aß occurs via efflux by P-glycoprotein (P-gp, gene product of the multidrug resistance protein 1, MDR1) and the low-density lipoprotein receptor-related protein 1 (LRP1) at the blood brain barrier; Aß returns to the brain via the receptor for advanced glycation end products (RAGE). Other efflux transporters - the breast cancer resistance protein (BCRP) and multidrug resistance associated proteins (MRP1/4) - also facilitate Aß efflux from brain. Aß is degraded mostly by neprilysin, then the insulin degrading enzyme, and is phagocytosed by the microglia. With normal and pathological aging, ß-secretase protein (BACE-1) is elevated towards the amyloidogenic pathway and neprilysin, P-gp, LRP1 and vitamin D levels are decreased, and RAGE, elevated. High cholesterol levels catalyze Aß42 formation and render lower CYP46A1 expression in brain that benefits brain BACE-1 activity. Although the peripheral and brain cholesterol are independent pools, peripheral but not brain cholesterol levels correlate strongly with brain Aß accumulation. The guinea pig (GP) is chosen for study. Its size is well-suited for serial plasma and CSF collection. There is 100% sequence correspondence of the GP Aß peptide and a high homology of the Mdr1 with that in humans. The GP carries most of its cholesterol in low density lipoprotein and possesses cholesterol ester transfer protein and lipoprotein lipase activities that result in reverse cholesterol transport and delipidation cascades similar to those in men. This proposed program focuses on defining the cellular changes in GP enzymes and transporters that form and remove Aßs with aging and altered vitamin D/cholesterol status, and the scientific investigation falls under the purview of NSERC. We will Aim 1: develop an improved method to assay for Aß40 and Aß42 by solid phase extraction, SPE-ELISA Aim 2: examine the changes in genes involved in Aß homeostasis among GPs of different ages, sexes, and vitamin D/cholesterol status Aim 3: examine the pharmacokinetics of Aß in brain and liver among GPs of different ages, sexes, and vitamin D/cholesterol status Aim 4: develop a physiologically-based pharmacokinetic model for the prediction of Aß changes in aging and altered vitamin D/cholesterol status  The aims collectively test the hypothesis that age, vitamin D deficiency and high cholesterol are risk factors for Aß accumulation in the brain. The scientific data will lead to remedial measures to ameliorate the outcomes to improve brain health.