Alzheimer’s disease (AD), the most prevalent disease of aged people, is a progressive neurodegenerative disorder with dementia. Amyloid-ß (also known as ß-protein and referred to here as Aß) is a well-established, seminal peptide in AD that is produced from the amyloid precursor protein (APP) by consecutive digestion with the ß secretase of BACE (beta-site amyloid cleaving enzyme) and gamma secretase of the presenilin complex. Abnormal cerebral accumulation of Abeta in the form of insoluble fibrils in senile plaques and cerebral amyloid angiopathy (CAA) is a neuropathological hallmark of AD. In contrast to insoluble fibrillary Aß, a soluble oligomeric complex, ADDL, consists of low-n oligomers of Aß, such as Aß*56. Despite their different names, it is currently proposed that oligomeric Aß is directly involved in synaptic toxicity and cognitive dysfunction in the early stages of AD. This chapter identifies a novel APP mutation (E693delta; referred to as the Osaka mutation) in a pedigree with probable AD, resulting in a variant Aß lacking glutamate at position 22. Based on theoretical predictions and in vitro studies on synthetic mutant Aß peptides, the mutated Aß peptide showed a unique and enhanced oligomerization activity without fibrillization. This was further confirmed by PiB-PET analysis on the proband patient. Collectively, the chapter concludes that the Osaka mutation is the first human evidence for the hypothesis that oligomeric Aß is involved in AD.
TopI. Introduction
Alzheimer’s disease (AD) is a well-known, progressive neurodegenerative disorder with dementia. The neuropathological features of AD include senile plaques and neurofibrillary tangles in addition to cerebral atrophy from massive neuronal loss. Amyloid-β (also known as β-protein and referred to here as Aβ) is a well-established, seminal peptide in AD that is produced from the amyloid precursor protein (APP) by consecutive digestion with the β-secretase of BACE and gamma-secretase of the presenilin complex. Abnormal cerebral accumulation of Aβ in the form of insoluble fibrils in senile plaques and cerebral amyloid angiopathy (CAA) is widely believed to cause AD. In contrast to insoluble Aβ fibrils, a soluble, nonfibrillary oligomeric complex is currently claimed as a new pathological Aβ species. It has been termed ADDLs (Lambert et al, 1998), low-n oligomer Aβ, dimer (Walsh et al, 2002), Abeta*56 (Lesne et al, 2006) (here, Aβ oligomer collectively together). Despite these different names, it has recently been proposed that Aβ oligomer directly causes synaptic toxicity and cognitive dysfunction in the early stages of AD (Selkoe, 2002). To discuss Aβ oligomers in depth here, the relationship among ADDLs, Aβ oligomer, single oligomers of Aβ (mainly the dimeric form), and Aβ*56 should be explained. It is not easy to compare one Aβ oligomer with other morphologically characterized nonfibrillary Aβ species such as protofibrils (Walsh, Lomakin, Benedek, Condron, & Teplow, 1997), Globulomer (Gellermann et al, 2008), AβO (Kayed et al, 2003), Paranucleus (Bitan, Kirkitadze, Lomakin, Vollers, Benedek & Teplow, 2003), Annulus (Caughey & Lansbury, 2003), amyloidspheroid (Hoshi, 2003), β amyball (Westlind-Danielsson & Arnerup, 2001), (for review in detail, see [Roychaudhuri, Yang, Hoshi & Teplow, 2009]). With these views, new concepts focusing on nonfibrillary and soluble Aβ complex based on synaptic dysfunction are emerging regarding the cause of AD. Here, I review and discuss the Aβ oligomer, particularly based on our current knowledge of patients with early onset familial AD as the sole human evidence in support of the so-called “oligomer hypothesis” and its importance to advancing the research of AD etiology.