Sarah J. Schonberger 1 Paul F. Edgar 2 Robert Kydd 1 Richard L. M. Faull 1 Garth J. S. Cooper 1 1 University of Auckland 2 Christchurch Medical School, New Zealand Proteomic analysis of the brain in Alzheimer’s disease: Molecular phenotype of a complex disease process Alzheimer’s disease (AD) is a progressive neurodegenerative disorder accounting for about 50% of all dementias, yet its pathogenic mechanisms remain poorly understood. In order to provide a more complete picture of pathogenesis in AD, we analysed six human brain regions for alterations in their proteomes. Quantitative proteome analysis was used to compare signals corresponding to individual proteins between post mor- tem brain tissues from persons with AD, and those from age-matched nondemented control (NC) tissues. In severely injured brain regions, 76 proteins were differentially expressed in AD hippocampus compared with NC, 62 proteins were differentially expressed in temporal cortex, and 39 proteins were differentially expressed in entor- hinal cortex. Significant differences were also present in relatively spared regions. Thus, 34 proteins were differentially expressed in AD cerebellum compared with NC, 125 proteins were differentially expressed in cingulate gyrus, and 75 proteins were differentially expressed in sensorimotor cortex. The identity of 37 of these proteins was determined, and the possible relevance of changes in key pathogenic pathways analysed. These studies provide a unique snapshot illustrating the complexity of inter- related disease mechanisms at work in a complex, multifactorial disease, and show that comparative proteome analysis is a method with the power to develop important new insights into pathogenic mechanisms in the dementias. Keywords: Comparative proteome analysis / Two-dimensional gel electrophoresis / Dementia / Phenotypic analysis / Disease mechanism PRO 0157 1 Introduction Alzheimer’s disease (AD) is a progressive neurodegenera- tive disorder accounting for about 50% of all dementias. Pathologically, the AD brain is characterized by two types of lesions: neuritic plaques composed mainly of the amy- loid beta (Ab) protein, and neurofibrillary tangles com- posed mainly of a hyperphosphorylated form of the pro- tein tau (t). Because of this pathology, two major hypoth- eses have been proposed. According to the amyloid cascade hypothesis, neurodegeneration in AD begins with the abnormal processing of the amyloid precursor protein (APP) and results in the production, aggregation and deposition of Ab [1]. Amyloid deposits in themselves are not sufficient to cause AD, however it is emerging that the toxicity of amyloid beta occurs when it is in a nonfibril- lar form, before plaques are formed. The amyloid cascade must then be able to facilitate neurofibrillary tangle forma- tion and cell death. According to the neuronal cytoskele- tal degeneration hypothesis, cytoskeletal changes are the main events that lead to neurodegeneration in AD, as the hyperphosphorylation and aggregation of t are related to the activation of cell death processes [1]. Neurofibrillary tangles in themselves are not sufficient to cause AD, yet it is becoming apparent that cognitive deficits may not occur until neurofibrillary tangles have been formed. The greatest risk factor currently identified in AD is age. The early-onset form of AD, which develops between 40– 65 years of age, is primarily familial and accounts for up to 10% of all cases. Mutations in the APP gene account for up to 5% of familial cases, and mutations in presenilin genes 1 and 2 account for up to 80% of familial cases [2]. Mutations in APP and presenilins 1 and 2 are associated with increased concentrations of Ab, and presenilins appear to have a critical role in Ab processing [3]. The late-onset form of AD develops after 65 years of age and the majority of cases are sporadic. Apolipoprotein E (Apo E) has been established as a major risk factor in late-onset AD. The epsilon 4 (e4) allele is associated with increased deposition of Ab in the brain and homozygosity for this allele increases the risk of sporadic AD at least eightfold [3]. The genetic risk factors currently implicated in AD are not sufficient to cause the disease, but may greatly increase the risk above that of the general population. Correspondence: Professor Garth J. S. Cooper, School of Bio- logical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand E-mail: g.cooper@auckland.ac.nz Fax: +64-9-373-7045 Abbreviations: Aâ, amyloid b-protein; AD, Alzheimer’s disease; apo E, apolipoprotein E; NC, nondemented control Proteomics 2001, 1, 1519–1528 1519 ª WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001 1615-9853/01/1211–1519 $17.50+.50/0