＜Symposium IV＞Oligomeric Aβ is the sole culprit molecule to cause Alzheimer's disease?

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Alzheimer's disease (AD) is the major and common disease usually for aged people to show progressiveneurodegenerative disorder with the dementia. Amyloid-beta （also β-protein and referred here to as Aβ） is a wellestablishedseminal peptide in AD that is produced from the amyloid precursor protein （APP） by consecutivedigestions with β-secretase of BACE and gamma-secretase of the presenilin complex. Abnormal cerebralaccumulation of Aβ such as insoluble fi brils in senile plaques and cerebral amyloid angiopathy （CAA） are observedas a neuropathological hallmark of AD. In contrast to such insoluble fi brillary Aβ, a soluble oligomeric complex isdiscussed as ADDLs, Aβ oligomer, low-n oligomer Aβ, Aβ*56 or so. Despite their diff erent names, it is proposed asthe current hypothesis that oligomeric Aβ is the direct molecule to cause synaptic toxicity and cognitive dysfunctionin the early stages of AD. We identifi ed a novel APP mutation （E693delta; referred to as the Osaka mutation） in apedigree with probable AD resulting in a variant Aβ lacking glutamate at position 22. Based on theoretical predictionand in vitro studies on synthetic mutant Aβ peptides, the mutated Aβ peptide showed a unique aggregation propertyof enhanced oligomerization but no fi brillization. This was further confi rmed by PiB-PET analysis on the probandpatient. Collectively together, we conclude that the Osaka mutation is the fi rst human evidence for the hypothesisthat oligomeric Aβ is involved in AD.

＜Symposium IV＞Oligomeric Aβ is the sole culprit molecule to cause Alzheimer's disease?

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