Alzheimer’s Pathogenesis and Diagnostics (Modified Neural Proteome in Alzheimer’s Diseased Tissue)

Alzheimer’s disease (AD) is a progressive neurodegenerative disease responsible for approximately 50% of dementia cases. It is both emotionally and economically devastating. Although increased age is clearly the most significant risk factor, the pathogenesis of AD is still not completely understood. Previous work has shown a number of attributes shared by both familial and sporadic AD. Mutations in the genes for b APP, presenilin-1 or -2, account for nearly all of the early-onset familial cases of AD. Most late-onset AD is sporadic yet subject to genetic influences, including the e 4 allele of apolipoprotein E and a haplotype of polymorphisms in proinflammatory cytokine loci. Therefore, the ongoing development or pathogenesis of the disease is clearly a complex pathway involving numbers of complex mechanisms, most likely both genetic and physiological. New pathogenic mechanisms continue to be suggested by various methodologies. Most hypotheses include an overproduction or accumulation of the 42-amino acid form of the amyloid b -peptide, produced from b APP by the b - and g -secretases. However, there is also evidence for aberrant phosphorylation, non-enzymatic glycosylation, oxidation, nitrosylation, and other posttranslational modifications of multiple proteins. Thus, critical insights might be gleaned from additional understanding of protein levels and alterations.

A better understanding of the pathogenic mechanisms at work in AD can only aid efforts toward early diagnosis and development of effective therapies. Currently, analysis of the human condition at its end-stage presents an overwhelming array of variability and extensive deterioration. Even staged analysis of progression in animal models can be hamstringed by the biases of rational supposition, and a more open-ended exploration could identify events and molecules heretofore overlooked. Gene arrays represent one such unbiased survey approach but are limited by the disconnect between mRNA levels and protein expression, not to mention the inability to detect post-translational modifications. For these reasons, validation of proteomic techniques is warranted.