title: Alzheimer's disease: the two-hit hypothesis.
abstract: There are many lines of evidence showing that oxidative stress and aberrant mitogenic changes have important roles in the pathogenesis of Alzheimer's disease (AD). However, although both oxidative stress and cell cycle-related abnormalities are early events, occurring before any cytopathology, the relation between these two events, and their role in pathophysiology was, until recently, unclear. However, on the basis of studies of mitogenic and oxidative stress signalling pathways in AD, we proposed a "two-hit hypothesis" which states that although either oxidative stress or abnormalities in mitotic signalling can independently serve as initiators, both processes are necessary to propagate disease pathogenesis. In this paper, we summarise evidence for oxidative stress and abnormal mitotic alterations in AD and explain the two-hit hypothesis by describing how both mechanisms are necessary and invariant features of disease.
authors.affiliation: Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Raina
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D000682:Amyloid / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D008040:Genetic Linkage; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D053764:Presenilin-1; D053766:Presenilin-2; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000682:Amyloid; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2