Neurobiology of Aging 23 (2002) 1051–1072 Open peer commentary A as a bioflocculant: implications for the amyloid hypothesis of Alzheimer’s disease Stephen R. Robinson ∗ , Glenda M. Bishop 1 Department of Psychology, Monash University, Clayton, Vic. 3800, Australia Received 13 July 2001; received in revised form 20 September 2001; accepted 20 November 2001 Abstract Research into Alzheimer’s disease (AD) has been guided by the view that deposits of fibrillar amyloid- peptide (A) are neurotoxic and are largely responsible for the neurodegeneration that accompanies the disease. This ‘amyloid hypothesis’ has claimed support from a wide range of molecular, genetic and animal studies. We critically review these observations and highlight inconsistencies between the predictions of the amyloid hypothesis and the published data. We show that the data provide equal support for a ‘bioflocculant hypothesis’, which posits that A is normally produced to bind neurotoxic solutes (such as metal ions), while the precipitation of A into plaques may be an efficient means of presenting these toxins to phagocytes. We conclude that if the deposition of A represents a physiological response to injury then therapeutic treatments aimed at reducing the availability of A may hasten the disease process and associated cognitive decline in AD. © 2002 Published by Elsevier Science Inc. Keywords: Amyloid- peptide; Amyloid hypothesis; Amyloid precursor protein; Apolipoprotein E; Bioflocculant hypothesis; Familial Alzheimer’s disease; Presenilin; Secretase; Transgenic mice; Toxicity 1. Introduction Alzheimer’s disease (AD) is the most common cause of dementia in the aged and is a significant cause of mortality in affected individuals. The causes of this devastating dis- ease have not been established but valuable insights have been gained concerning the involvement of amyloid- (A) peptide, which is formed when amyloid precursor protein (APP) is cleaved by intracellular - and -secretases. Once cleaved, A can be secreted into the extracellular fluid. The A can then diffuse into the cerebrospinal fluid (CSF) or coalesce into a deposit of loosely arranged A peptide, known as a ‘diffuse plaque’. Such plaques are thought to be harmless but as the amyloid deposit matures, the A reorganizes into fibrils that have a -pleated sheet confor- mation and are birefringent when stained with Congo red. An important observation has been that plaques composed of fibrillar A often contain dystrophic neurites and are known as ‘neuritic plaques’ [63]. The spatial distribution and number of neuritic plaques in AD have been correlated with the extent of cognitive loss [66]. ∗ Corresponding author. Tel.: +61-3-990-53903; fax: +61-3-990-53948. E-mail address: stephen.robinson@med.monash.edu.au (S.R. Robinson). 1 Present address: Institute of Pathology Case Western Reserve Univer- sity, Cleveland. These observations and others have contributed to the prevailing view that fibrillar A is neurotoxic and is largely responsible for the pathogenesis in AD. This view has be- come known as the ‘amyloid hypothesis’, and variants of this hypothesis have guided most of the research into AD pathogenesis during the past decade [115,238,247]. The amyloid hypothesis (Fig. 1) posits that an altered proteol- ysis of APP leads to a gradual accumulation of A42 in the interstitial fluid of the brain. A42 oligomerizes and deposits into diffuse plaques, providing a focus for the subsequent deposition of A40 and other proteins. This ac- cumulation of toxic fibrillar A injures neurites within the plaques and in the surrounding neuropil. This focal injury disrupts neuronal function and homeostasis and eventually causes neuronal death. As increasing numbers of neuritic plaques are formed there is a cascade of neuronal loss that results in dementia. In this view, familial AD is caused by genetic mutations that directly lead to the overproduction of A, while sporadic AD is caused by genetic and/or envi- ronmental factors that predispose the brain to an increased production, or a reduced rate of clearance, of A. The amyloid hypothesis is based on the premise that fib- rillar A is neurotoxic and this important role has stimulated intense scientific investigation of this peptide. These investi- gations have yielded valuable insights into the nature of A. The bulk of these new observations appear to be consistent 0197-4580/02/$ – see front matter © 2002 Published by Elsevier Science Inc. PII:S0197-4580(01)00342-6