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Alzheimer's disease: the two-hit hypothesis.
Xiongwei Zhu1, Arun K Raina, George Perry
1Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
The Lancet. Neurology
|March 25, 2004
Summary
Oxidative stress and abnormal cell division are early events in Alzheimer's disease (AD). Our two-hit hypothesis proposes both are necessary to drive AD pathogenesis, even if one initiates.
Area of Science:
- Neuroscience
- Pathology
- Molecular Biology
Background:
- Oxidative stress and aberrant mitogenic changes are implicated in Alzheimer's disease (AD) pathogenesis.
- These events occur early, preceding visible cellular damage.
Purpose of the Study:
- To explore the relationship between oxidative stress and cell cycle abnormalities in AD.
- To propose and explain the "two-hit hypothesis" for AD pathogenesis.
Main Methods:
- Review of signaling pathways related to oxidative stress and mitogenic changes in AD.
- Synthesis of evidence supporting the proposed hypothesis.
Main Results:
- Both oxidative stress and abnormal mitotic signaling are early events in AD.
- Evidence supports the "two-hit hypothesis" where both factors are required for disease propagation.
Conclusions:
- Oxidative stress and aberrant cell cycle regulation are critical, interacting components of Alzheimer's disease.
- The "two-hit hypothesis" provides a framework for understanding the invariant mechanisms driving AD pathogenesis.