Reexamining Alzheimer's Disease: Evidence for a Protective Role for Amyloid-β Protein Precursor and Amyloid-β

Issue title: Mini-Forum: Roles of Amyloid-β and Tau Phosphorylation in Neuronal Repair and Protection

Guest editors: Garth Bissette

Article type: Research Article

Authors: Castellani, Rudy J.^{a; *} | Lee, Hyoung-gon^b | Siedlak, Sandra L.^b | Nunomura, Akihiko^c | Hayashi, Takaaki^d | Nakamura, Masao^e | Zhu, Xiongwei^b | Perry, George^{b; f} | Smith, Mark A.^{b; *}

Affiliations: [a] Department of Pathology, University of Maryland, Baltimore, MD, USA | [b] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA | [c] Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Yamanashi, Japan | [d] Hokkaido Institute of Public Health, Kita 19, Nishi 12, Kita-ku, Sapporo, Japan | [e] Department of Chemistry, Asahikawa Medical College, Asahikawa, Japan | [f] College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA | Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA

Correspondence: [*] Corresponding authors: Mark A. Smith, Ph.D., Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA. Tel.: +1216 368 3670; Fax: +1 216 368 8964; E-mail: mark.smith@case.edu. Rudy J. Castellani, M.D., Division of Neuropathology, Department of Pathology, University of Maryland, 22 South Greene Street, Baltimore, MD 21201, USA. Tel.: +1 410 328 5555; Fax: +1 410 328 5508; E-mail: rcastellani@som.umaryland.edu.

Note: [] Handling Editor: Jesus Avila

Abstract: Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-β-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-β as the major pathogenic mechanism with the ultimate goal of using amyloid-β lowering therapies as an avenue of treatment. Unfortunately, nearly a quarter century later, no tangible progress has been offered, whereas spectacular failure tends to be the most compelling. We have long contended, as has substantial literature, that proteinaceous accumulations are simply downstream and, often, endstage manifestations of disease. Their overall poor correlation with the level of dementia, and their presence in the cognitively intact is evidence that is often ignored as an inconvenient truth. Current research examining amyloid oligomers, therefore, will add copious details to what is, in essence, a reductionist distraction from upstream pleiotrophic processes such as oxidative stress, cell cycle dysfunction, and inflammation. It is now long overdue that the neuroscientists avoid the pitfall of perseverating on “proteinopathies” and recognize that the continued targeting of end stage lesions in the face of repeated failure, or worse, is a losing proposition.

Keywords: Alzheimer's disease, amyloid, amyloid-β protein precursor (AβPP) processing, antioxidant, cellular toxicity, oligomers, oxidative stress

DOI: 10.3233/JAD-2009-1151

Journal: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 447-452, 2009