title: Neurofibrillary degeneration of the Alzheimer-type: an alternate pathway to neuronal apoptosis?
abstract: Neuronal death is a process which may be either physiological or pathological. Apoptosis and necrosis are two of these processes which are particularly studied. However, in neurodegenerative disorders, some neurons escape to these types of death and "agonize" in a process referred to as neurofibrillary degeneration. Neurofibrillary degeneration is characterized by the intraneuronal aggregation of abnormally phosphorylated microtubule-associated Tau proteins. A number of studies have reported a reactivation of the cell cycle in the neurofibrillary degeneration process. This reactivation of the cell cycle is reminiscent of the initiation of apoptosis in post-mitotic cells where G1/S markers including cyclin D1 and cdk4/6, are commonly found. However, in neurons exhibiting neurofibrillary degeneration, both G1/S and G2/M markers are found suggesting that they do not follow the classical apoptosis and an aberrant cell cycle occurs. This aberrant response leading to neurofibrillary degeneration may be triggered by the sequential combination of three partners: the complex Cdk5/p25 induces both apoptosis and the "abnormal mitotic Tau phosphorylation". These mitotic epitopes may allow for the nuclear depletion of Pin1. This latter may be responsible for escaping classical apoptosis in a subset of neurons. Since neurofibrillary degeneration is likely to be a third way to die, molecular mechanisms leading to changes in Tau phosphorylation including activation of kinases such as cdk5 or other regulators such as Pin1 could be important drug targets as they are possibly involved in early stages of neurodegeneration.
authors.affiliation: INSERM U422, Institut de Médecine Prédictive et Recherche Thérapeutique, Place de Verdun, F-59045 Lille Cedex, France.
authors.forename: Malika
authors.initials: M
authors.lastname: Hamdane
authors.forename: Patrice
authors.initials: P
authors.lastname: Delobel
authors.forename: Anne-Véronique
authors.initials: AV
authors.lastname: Sambo
authors.forename: Caroline
authors.initials: C
authors.lastname: Smet
authors.forename: Séverine
authors.initials: S
authors.lastname: Bégard
authors.forename: Anne
authors.initials: A
authors.lastname: Violleau
authors.forename: Isabelle
authors.initials: I
authors.lastname: Landrieu
authors.forename: André
authors.initials: A
authors.lastname: Delacourte
authors.forename: Guy
authors.initials: G
authors.lastname: Lippens
authors.forename: Stéphane
authors.initials: S
authors.lastname: Flament
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D006801:Humans; D008938:Mitosis; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009410:Nerve Degeneration / Q000473:pathology*; D016874:Neurofibrillary Tangles / Q000473:pathology; D019696:Peptidylprolyl Isomerase / Q000502:physiology; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016875:tau Proteins; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase