title: Neuron-specific alterations in signal transduction pathways associated with Alzheimer's disease.
abstract: The hallmarks of sporadic Alzheimer's disease (AD) are extracellular amyloid deposits, intracellular neurofibrillary tangles (NFTs), and neuronal death. Hyperphosphorylation of tau is a key factor in the generation of NFTs. Mitogen activated protein kinase 1 (MAPK1) and protein kinase C beta (PRKCB) are thought to play a role in hyperphosphorylation, and PRCKB is thought to be involved in hypoxic stress and vascular dysfunction, and to trigger MAPK phosphorylation pathways. We performed single-cell analyses of neurons with different vulnerabilities to AD-related changes. Using quantitative PCR (qPCR), we measured the levels of MAPK1 and PRKCB transcript in CA1 (high vulnerability), CA2 pyramidal cells from the hippocampus, granule cells from the cerebellum (low vulnerability), and neurons from the brain stem (nucleus tractus spinalis nervi trigemini, characterized by early neurophysiological deficits) at progressive Braak stages compared to age-matched controls. The highly vulnerable CA1 pyramidal neurons were characterized by age- and disease-unrelated increases in PRCKB levels and by age- and disease-related increases in MAPK1 levels. In contrast, low PRKCB levels were found in CA2 pyramidal neurons, and MAPK1 levels were elevated in controls and intermediate AD stages. Both PRKCB and MAPK1 were increased in the late AD stages. MAPK1 and PRKCB levels were low in the brainstem and cerebellum. We propose that alterations in the expression of these two genes occur early in the pathogenesis of AD in a region-specific manner. In addition, multiple signal transduction pathways need to be affected to result in AD instead of physiological aging.
authors: Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.
authors: Anne
authors: A
authors: Gerschütz
authors: University Hospital, Clinic and Policlinic for Psychiatry, Psychosomatic and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors: Helmut
authors: H
authors: Heinsen
authors: Clinic of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland.
authors: Edna
authors: E
authors: Grünblatt
authors: Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.
authors: Anne Kristin
authors: AK
authors: Wagner
authors: Clinic of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland.
authors: Jasmin
authors: J
authors: Bartl
authors: Department of Forensic Medicine, University of Schleswig-Holstein, Luebeck, Germany.
authors: Christoph
authors: C
authors: Meissner
authors: Clinic and Policlinic for Psychiatry and Psychotherapy, University of Tuebingen, Tuebingen, Germany.
authors: Andreas J
authors: AJ
authors: Fallgatter
authors: MRC London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
authors: Safa
authors: S
authors: Al-Sarraj
authors: MRC London Neurodegenerative Diseases Brain Bank, King's College London, London, UK.
authors: Claire
authors: C
authors: Troakes
authors: Institut de Neuropatologia, Seervei Anatomia Patologica, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain.
authors: Isidro
authors: I
authors: Ferrer
authors: Institute of Neuropathology and Prion Research, University of Munich, Munich, Germany.
authors: Thomas
authors: T
authors: Arzberger
authors: University Hospital, Clinic and Policlinic for Psychiatry, Psychosomatic and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors: Jürgen
authors: J
authors: Deckert
authors: University Hospital, Clinic and Policlinic for Psychiatry, Psychosomatic and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors: Peter
authors: P
authors: Riederer
authors: University Hospital, Clinic and Policlinic for Psychiatry, Psychosomatic and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
authors: Matthias
authors: M
authors: Fischer
authors: Institute of Legal Medicine, University of Wuerzburg, Wuerzburg, Germany.
authors: Thomas
authors: T
authors: Tatschner
authors: Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Wuerzburg, Germany.
authors: Camelia Maria
authors: CM
authors: Monoranu
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D061346:Laser Capture Microdissection; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D064546:Protein Kinase C beta / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; C579054:PRKCB protein, human; D064546:Protein Kinase C beta; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1
keywords: Alzheimer's disease; MAPK1; PRKCB; neurodegeneration; selective vulnerability; signal transduction pathway