title: Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis.
abstract: The classic neuropathological diagnostic markers for AD are amyloid plaques and neurofibrillary tangles, but their role in the etiology and progression of the disease remains incompletely defined. Research over the last decade has revealed that cell cycle abnormalities also represent a major neuropathological feature of AD. These abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles; and it has been suggested that neuronal cell cycle regulatory failure may be a significant component of the pathogenesis of AD. The amyloid precursor protein (APP) is most commonly known as the source of the beta-amyloid (Abeta) peptides that accumulate in the brains of patients with AD. However, a large body of work supports the idea that APP is also a signaling receptor. Most recently, it has been shown that familial AD (FAD) mutations in APP or simple overexpression of wild type APP cause dysfunction of APP signaling, resulting in initiation of DNA synthesis in neurons and consequent apoptosis. In this article, we review the evidence that APP has the potential to activate aberrant neuronal cell cycle re-entry in AD, and we describe a signal transduction pathway that may mediate this abnormal activation of the cell cycle.
authors.affiliation: Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478, USA. neve@helix.mgh.harvard.edu
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.forename: Donna L
authors.initials: DL
authors.lastname: McPhie
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D017209:Apoptosis; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D002453:Cell Cycle; D004247:DNA / Q000096:biosynthesis*; D004261:DNA Replication / Q000502:physiology*; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000201:enzymology* / Q000502:physiology; D012016:Reference Values; D015398:Signal Transduction
chemical_list: D016564:Amyloid beta-Protein Precursor; D004247:DNA