A Conceptual Analysis over Alzheimer's Disease

Introduction

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that destroys memory and thinking skills. As the disease progresses plaques and tangles form and spread through the cortex. These plaques are deposits of a protein fragment called beta-amyloid that builds up in the spaces between nerve cells. Tangles are twisted fibers of another protein called tau that builds up inside the cells. Currently it is unknown exactly what role plaques and tangles play in the disease but they are suspected to play a role in blocking communication between nerve cells and disrupting processes that cells need to survive.

The disease currently has no cure but research for symptoms and causes of the disease are ongoing. Several risk factors that increase the chance of developing the disease have been found. Although age is the strongest risk factor of developing the disease, genetics play a large part in increasing an individual's risk of developing AD. There are deterministic genes and risk genes.

Deterministic genes

Directly cause the disease, guaranteeing that anyone who inherits them will develop the disorder. Variations in genes that directly cause AD have been found. These include genes that code for three proteins: amyloid precursor protein (APP), presenilin-1 (PS-1) and presenilin-2 (PS-2).

Risk genes

Increase the likelihood of developing a disease, but do not guarantee it will happen. There are several risk genes that have been identified that have associations with AD. This project will emphasize analyzing the amino acid composition of the risk-increasing genes and possible interactions between these genes.

What is APOE?

Function

APOE gene provides instructions for making a protein called apolipoprotein E. This protein is a major apoproteins of the chylomicron. APOE binds to a specific liver and peripheral cell receptor and is essential in the normal catabolism of triglyceride-rich lipoprotein constituents. APOE combines with fats (lipids) in the body to form molecules called lipoproteins. Lipoproteins package cholesterol, along with other fats, and carry them through the bloodstream. The major alleles for the APOE gene are e2, e3, and e4 - the most common allele is e3, found in more than half of the general population.

Sub-cellular Localization

APOE maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes.

Cytogenic Location: 19q13.32 (long q arm of Chromosome 19 at position 13.32)

Molecular Location: Base pairs 44,905,749 to 44,909,395 on Chromosome 19 (Homo Sapiens)

Post-Translational Modification(s)

• Glycated in plasma VLDL of normal subjects, and of hyperglycemic diabetic patients at a higher level (2-3 fold).
  • P02649-APOE_HUMAN
• Phosphorylated by FAM20C in the extracellular medium.
  • P02649-APOE_HUMAN
• Synthesized with the sialic acid attached by O-glycosidic linkage and is subsequently desialylated in plasma. O-glycosylated with core 1 or possibly core 8 glycans. Thr-307 and Ser-314 are minor glycosylation sites compared to Ser-308.
  • P02649-APOE_HUMAN
• Glycosylation at Thr26, posLast=3636, posLast=9393, Thr212, posLast=307307, posLast=308308, and Ser314
  • NX_P02649

Structure

Three-dimensional structure of regions of APOE, highlighting iso-form differences