Mechanisms of Neuronal Degeneration in Alzheimer's Disease
1996; Cell Press; Volume: 16; Issue: 5 Linguagem: Inglês
10.1016/s0896-6273(00)80115-4
ISSN1097-4199
Autores Tópico(s)Tryptophan and brain disorders
ResumoAlzheimer's disease (AD) is the most common cause of progressive cognitive decline in the aged population. The triad of amyloid plaques, neurofibrillary tangles, and dementia that characterize AD was first described by Alois Alzheimer in 1907. Despite considerable progress in elucidating the molecular components of the brain lesions, the mechanism of neuronal degeneration in AD has been unclear. However, recent advances in molecular genetics have focused attention on several pathogenic mechanisms. There are now four different genes that confer susceptibility to AD—the amyloid precursor protein (APP), apolipoprotein E (ApoE), and two novel seven transmembrane domain proteins. Although it is likely that multiple molecular pathways can lead to AD, a central issue is whether all causes of the disease lead to a final common mechanism of neuronal death. This review describes recent advances in the molecular genetics and cell biology of AD and discusses the potential pathogenic mechanisms that emerge. Genetic and cell biological studies have implicated APP in the pathogenesis of AD. APP is a transmembrane glycoprotein that is the precursor of amyloid β (Aβ), a 40–42 amino acid peptide that is the principal constituent of senile plaques and cerebrovascular deposits in AD (Figure 1) (44Glenner G.G. Wong C.W. Alzheimer's disease initial report of the purification and characterization of a novel cerebrovascular amyloid protein.Biochem. Biophys. Res. Commun. 1984; 120: 885-890Crossref PubMed Google Scholar, 89Masters C.L. Simms G. Weinman N.A. Multhaup G. McDonald B.L. Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome.Proc. Natl. Acad. Sci. USA. 1985; 82: 4245-4249Crossref PubMed Google Scholar, 59Kang J. Lemaire H.-G. Unterbeck A. Salbaum J.M. Masters C.L. Grzeschik K.H. Multhaup G. Beyreuther K. 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APPs also appears to mediate the neurite outgrowth response to nerve growth factor (NGF) in PC12 cells, raising the possibility that altered processing of APP could affect neuronal reponsiveness to neurotrophic factors (100Milward E.A. Papadopoulos R. Fuller S.J. Moir R.D. Small D. Beyreuther K. Masters C.L. The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth.Neuron. 1992; 9: 129-137Abstract Full Text PDF PubMed Scopus (267) Google Scholar). Several effects of APP on cell signaling have been described. APP can associate with heterotrimeric G proteins (111Nishimoto I. Okamato T. Matsuura Y. Takahashi S. Okamato T. Murayama Y. Ogata E. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein Go.Nature. 1993; 362: 75-79Crossref PubMed Google Scholar), and APPs can activate high conductance potassium channels (40Furukawa F. Barger S.W. Blalock E.M. Mattson M.P. Activation of K+ channels and suppression of neuronal activity by secreted β-amyloid-precursor protein.Nature. 1996; 379: 74-78Crossref PubMed Scopus (251) Google Scholar) and increase the activity of MAP kinase (47Greenberg S.M. Koo E.H. Selkoe D.J. Qiu W.Q. Kosik K.S. Secreted β-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation.Proc. Natl. Acad. Sci. USA. 1994; 91: 7104-7108Crossref PubMed Scopus (119) Google Scholar). However, the relevance of these effects to the biological functions of APP has not been established. The biological functions of APP in vivo have recently been examined in homozygous APP-knockout mice. APP-knockout mice proceed through gestation normally, suggesting that APP is not absolutely required during development (179Zheng H. Jiang M. Trumbauer M.E. Sirinathsinghji D.J.S. Hopkins R. Smith D.W. Heavens R.P. Dawson G.R. Boyce S. Conner M.W. Stevens K.A. Slunt H.H. Sisodia S.S. Chen H.Y. 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