Amyloid Beta: The Alternate Hypothesis
Hyoung-gon Lee, Xiongwei Zhu, Akihiko Nunomura, George Perry and Mark A. Smith
Affiliation: Institute of Pathology, CaseWestern Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106USA.
Keywords: Alzheimer disease, amyloid beta, oxidative stress, pathogenesis
Alzheimer disease (AD) is a devastating condition and patients, caregivers, clinicians, and scientists are eager to decipher the underlying disease mechanism and, thereafter, target this therapeutically. Most investigators studying the underlying cause of AD have focused on amyloid-β (Aβ) such that the Amyloid Cascade Hypothesis is the predominant mechanism thought to be responsible for the disease. However, a number of caveats have led us to seriously question the validity of this hypothesis. First, in addition to increases in Aβ, genetic mutations in AD lead to increased vulnerability to oxidative/apoptotic insults indicating that the mutated protein disturbs redox balance. Whether mutations result in Aβ deposition that then causes oxidative stress or whether mutations cause oxidative stress that results in Aβ deposition is unclear. Indeed, while in vitro experiments show that Ab can directly cause oxidative stress to cells in culture, it is apparent from other studies that the reverse is also true, namely that oxidative stress leads to increases in Aβ. Notably, in vivo studies in both sporadic and genetic forms of the disease show that oxidative stress temporally precedes increases in Aβ and that increases in Aβ are associated with a decrease in oxidative stress. Based on these findings, we herein propose an Alternate Amyloid Hypothesis in which pathogenic factors for disease lead to increased oxidative stress that then leads to increases in Aβ. Further, we propose that Aβ serves as a redox sensor and that oxidatively-induced Ab serves to attenuate oxidative stress. Obviously, whether Ab is the culprit, as argued by the Amyloid Cascade Hypothesis, or a much maligned protector, as argued by the Alternate Amyloid Hypothesis, is clearly important to decipher to advance our understanding and design efficacious therapeutics for this disease.
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