β-Secretases, Alzheimer’s Disease, and Down Syndrome

Robin L Webb,M Paul Murphy

doi:10.1155/2012/362839

Abstract

Individuals with Down Syndrome (DS), or trisomy 21, develop Alzheimer's disease (AD) pathology by approximately 40 years of age. Chromosome 21 harbors several genes implicated in AD, including the amyloid precursor protein and one homologue of the β-site APP cleaving enzyme, BACE2. Processing of the amyloid precursor protein by β-secretase (BACE) is the rate-limiting step in the production of the pathogenic Aβ peptide. Increased amounts of APP in the DS brain result in increased amounts of Aβ and extracellular plaque formation beginning early in life. BACE dysregulation potentially represents an overlapping biological mechanism with sporadic AD and a common therapeutic target. As the lifespan for those with DS continues to increase, age-related concerns such as obesity, depression, and AD are of growing concern. The ability to prevent or delay the progression of neurodegenerative diseases will promote healthy aging and improve quality of life for those with DS.

Highlights

According to the CDC, 1 in 700 infants born have Down syndrome (DS), approximately 400,000 people in the US and 6 million people world-wide
Studying familial AD (FAD) gene mutations has provided insight into the molecular mechanisms that lead to neuropathology [9,10,11,12], even though the process may begin as much as 20 years before the patient begins to present clinically with symptoms [13]
FAD-linked mutations in amyloid precursor protein (APP) generally result in an increase in Aβ42 production [25, 26]; this is thought to be the most toxic peptide species generated by this noncanonical APP processing pathway and leads to aggregation and formation of higher order structures including oligomers that damage neurons and induce pathogenesis [28]

Summary

Introduction

According to the CDC, 1 in 700 infants born have Down syndrome (DS), approximately 400,000 people in the US and 6 million people world-wide. This is usually due to improper segregation of chromosomes into daughter cells during meiosis I (Figure 1), nondisjunction in meiosis II occurs This results in gametes that have two copies of chromosome 21 (HSA 21), and upon fusion with another gamete, results in trisomy 21. We know that essentially all individuals with DS develop AD-like pathology by the fourth decade of life This predated the finding that an extra copy of chromosome 21 causes DS by almost 50 years [6]. Studying FAD gene mutations has provided insight into the molecular mechanisms that lead to neuropathology [9,10,11,12], even though the process may begin as much as 20 years before the patient begins to present clinically with symptoms [13]

The Molecular Neurobiology and Histopathology of AD

APP and Aβ

Findings

Conclusion