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Protein markers for Alzheimer disease in the frontal cortex and cerebellum

From The Sir James McCusker Alzheimer’s Disease Research Unit (Drs. Verdile, Milward, Tan, and Martins, A. Gnjec, J. Fonte, G. Veurink, K. Bates, and D. Lim), School of Psychiatry & Clinical Neurosciences, The University of Western Australia, Hollywood Private Hospital, Nedlands, WA, Australia; Centre for Aging and Alzheimer’s Disease (Drs. Verdile and Martins), School of Biomedical & Sports Science, Edith Cowan University, Joondalup, WA, Australia; Center for NeuroVirology and Cancer Biology (Dr. Miklossy), College of Science and Technology, Temple University, Philadelphia, PA; Division of Neuropathology (Dr. Miklossy), University Institute of Pathology, Lausanne, Switzerland; Department of Anatomy and Human Biology (Dr. Dharmarajan, K. Bates, R. Lareu, and D. Lim), University of Western Australia, Nedlands, WA, Australia; Centre for Neuromuscular and Neurological Disorders (Dr. Kakulas), University of Western Australia, Nedlands, WA, Australia; Department of Immunology (Dr. Mehta), Institute for Basic Research in Developmental Disabilities, Staten Island, NY; Discipline of Medical Genetics (Dr. Milward), School of Biomedical Sciences MSB, Faculty of Health, University of Newcastle, Callaghan, NSW, Australia.

Address correspondence and reprint requests to Dr. Ralph Martins, The Sir James McCusker AD Research Unit, Department of Psychiatry & Clinical Neurosciences, The University of Western Australia, C/- Hollywood Private Hospital, Monash Avenue, Nedlands WA 6009, Australia; e-mail: rmartins{at}cyllene.uwa.edu.au

Objective: To compare proteins related to Alzheimer disease (AD) in the frontal cortex and cerebellum of subjects with early-onset AD (EOAD) with or without presenilin 1 (PS1) mutations with sporadic late-onset AD (LOAD) and nondemented control subjects.

Methods: Immunohistochemistry, immunoblot analysis, and ELISA were used to detect and assess protein levels in brain.

Results: In EOAD and to a lesser extent in LOAD, there was increased amyloid beta (Aß) deposition (by immunohistochemistry), increased soluble Aß (by immunoblot analysis), and specific increases in Aß₄₀ and Aß₄₂ (by ELISA) in the frontal cortex and, in some cases, in the cerebellum. Surprisingly, immunoblot analysis revealed reduced levels of PS1 in many of the subjects with EOAD with or without PS1 mutations. In those PS1 mutation-bearing subjects with the highest Aß, PS1 was barely, if at all, detectable. This decrease in PS1 was specific and not attributable solely to neuronal loss because amyloid precursor protein (APP) and the PS1-interacting protein ß-catenin levels were unchanged.

Conclusions: This study shows that in the frontal cortex and cerebellum from Alzheimer disease patients harboring certain presenilin 1 mutations, high levels of amyloid beta are associated with low levels of presenilin 1. The study provides the premise for further investigation of mechanisms underlying the downregulation of presenilin 1, which may have considerable pathogenic and therapeutic relevance.

Received September 9, 2003. Accepted in final form May 10, 2004.

*These authors contributed equally to this work.