Challenging the amyloid cascade hypothesis: senile plaques and amyloid-beta as protective adaptations to Alzheimer disease.
Ever since their initial description over a century ago, senile plaques and their major protein component, amyloid-beta, have been considered key contributors to the pathogenesis of Alzheimer disease. However, counter to the popular view that amyloid-beta represents an initiator of disease pathogenesis, we herein challenge dogma and propose that amyloid-beta occurs secondary to neuronal stress and, rather than causing cell death, functions as a protective adaptation to the disease. By analogy, individuals suffering from altitude sickness nearly always have elevated levels of hemoglobin. However, while hemoglobin is toxic to cells in culture and increased erythropoiesis at sea level can be deadly, it is clear that the increases in hemoglobin occurring at altitude are beneficial. Amyloid, like hemoglobin, may also be beneficial, in this case, following neuronal stress or disease. Although controversial, a protective function for amyloid-beta is supported by all of the available literature to date and also explains why many aged individuals, despite the presence of high numbers of senile plaques, show little or no cognitive decline. With this in mind, we suspect that current therapeutic efforts targeted toward lowering amyloid-beta production or removal of deposited amyloid-beta will only serve to exacerbate the disease process.
Lee
Hyoung-Gon
HG
Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Casadesus
Gemma
G
Zhu
Xiongwei
X
Takeda
Atsushi
A
Perry
George
G
Smith
Mark A
MA
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000502:physiology*; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D005609:Free Radicals; D006454:Hemoglobins / Q000737:chemistry; D006801:Humans; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D005609:Free Radicals; D006454:Hemoglobins