Reexamining Alzheimer's disease: Evidence for a protective role for amyloid-β protein precursor and amyloid-β

Department of Pathology, University of Maryland, Baltimore, MD 21201, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 3.61). 08/2009; 18(2):447-52. DOI: 10.3233/JAD-2009-1151
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized clinically by cognitive decline and pathologically by the accumulation of amyloid-beta-containing senile plaques and neurofibrillary tangles. A great deal of attention has focused, focused on amyloid-beta as the major pathogenic mechanism with the ultimate goal of using amyloid-beta 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.

Download full-text


Available from: George Perry, Jul 07, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: According to the amyloid cascade hypothesis, accumulation of the amyloid peptide Aβ, derived by proteolytic processing from the amyloid precursor protein (APP), is the key pathogenic trigger in Alzheimer's disease (AD). This view has led researchers for more than two decades and continues to be the most influential model of neurodegeneration. Nevertheless, close scrutiny of the current evidence does not support a central pathogenic role for Aβ in late-onset AD. Furthermore, the amyloid cascade hypothesis lacks a theoretical foundation from which the physiological generation of Aβ can be understood, and therapeutic approaches based on its premises have failed. We present an alternative model of neurodegeneration, in which sustained cholesterol-associated neuronal distress is the most likely pathogenic trigger in late-onset AD, directly causing oxidative stress, inflammation and tau hyperphosphorylation. In this scenario, Aβ generation is part of an APP-driven adaptive response to the initial cholesterol distress, and its accumulation is neither central to, nor a requirement for, the initiation of the disease. Our model provides a theoretical framework that places APP as a regulator of cholesterol homeostasis, accounts for the generation of Aβ in both healthy and demented brains, and provides suitable targets for therapeutic intervention.
    Ageing research reviews 07/2012; 12(1):282-288. DOI:10.1016/j.arr.2012.06.007 · 7.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The nervous system interacts directly with the endocrine system to control a plethora of central nervous system (CNS) functions. Metabolic and reproductive hormones are known to be important in the maintenance of neuronal health and their fluctuations are important for CNS aspects ranging from sleep and appetite regulation to cognitive function. This review will summarize and critically evaluate how age-related changes in sex and metabolic hormones modulate affect cognitive function and the implications of targeting the neuroendocrinological system as a therapeutic strategy in Alzheimer's disease.
    BioFactors 03/2012; 38(2):123-32. DOI:10.1002/biof.1011 · 3.00 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease is a 100-year-old concept. As a diagnostic label, it has evolved over the 20th and 21st centuries from a rare diagnosis in younger patients to a worldwide epidemic common in the elderly, said to affect over 35 million people worldwide. In this opinion piece, we use a constructivist approach to review the early history of the terms "Alzheimer's disease" and related concepts such as dementia, as well as the more recent nosological changes that have occurred in the four major editions of the Diagnostic and Statistical Manual since 1952. A critical engagement of the history of Alzheimer's disease and dementia, specifically the evolution of those concepts in the DSM over the past 100 years, raises a number of questions about how those labels and emergent diagnoses, such as Neurocognitive Disorders and Mild Cognitive Impairment, might continue to evolve in the DSM-V, due for release in 2013.
    Culture Medicine and Psychiatry 05/2011; 35(3):417-35. DOI:10.1007/s11013-011-9219-x · 1.29 Impact Factor