Alzheimer Disease: Britschgi M

Britschgi M, Wyss-Coray T. · Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5235, USA. · Arch Neurol. · Pubmed #19064741 No free full text.

Abstract: Alzheimer disease (AD) has become one of the main health concerns for the elderly population in the United States. Current treatments target symptoms only, but several advanced clinical trials are testing new drugs that are potentially disease modifying. Because AD is still difficult to diagnose in its earliest stages and the disease process is estimated to start many years before current clinical diagnosis is made, accurate and simple diagnostic tools are urgently needed. We recently described a blood-based panel of secreted signaling proteins that distinguishes between blinded samples from patients with AD and control subjects with high accuracy. The same proteins also predicted progression to AD in preclinical patients with mild cognitive impairment several years before clinical diagnosis for AD was made. Herein, we describe these findings and discuss the potential for a more general application of our proteomic approach in understanding and diagnosing disease.

Britschgi M, Wyss-Coray T. · Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA. · Int Rev Neurobiol. · Pubmed #17678963 No free full text.

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by a progressive cognitive decline and dementia. AD brains are marked by amyloid plaques and neurofibrillary tangles, neuronal cell loss, and a prominent activation of glial cells, and innate immune responses. A growing number of studies in AD have also reported alterations in systemic immune responses including changes in lymphocyte and macrophage distribution and activation, the presence of autoantibodies, or abnormal cytokine production. Studies in animal models for AD support the notion that immune cells infiltrate the brain and may modulate the disease. Here we will review evidence for systemic alterations in immune responses and a role for acquired immunity in AD and discuss their potential contribution to the disease.

Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B, Rockenstein E, Levine B, Wyss-Coray T. · Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. · J Clin Invest. · Pubmed #18497889 links to  free full text

Abstract: Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid beta (Abeta) accumulation, extracellular Abeta deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD.

Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, Friedman LF, Galasko DR, Jutel M, Karydas A, Kaye JA, Leszek J, Miller BL, Minthon L, Quinn JF, Rabinovici GD, Robinson WH, Sabbagh MN, So YT, Sparks DL, Tabaton M, Tinklenberg J, Yesavage JA, Tibshirani R, Wyss-Coray T. · Satoris, Inc., 2686 Middlefield Road, Suite E, Redwood City, California 94063, USA. · Nat Med. · Pubmed #17934472 No free full text.

Abstract: A molecular test for Alzheimer's disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer's and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer's disease 2-6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer's disease.

Britschgi M, Wyss-Coray T. · No affiliation provided · Nat Med. · Pubmed #17415372 No free full text.

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