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• W2054388625 abstract "Alzheimer's disease (AD), the most common cause of dementia among the elderly, may either represent the far end of a continuum that begins with age-related memory decline or a distinct pathobiological process. Although mice that faithfully model all aspects of AD do not yet exist, current mouse models have provided valuable insights into specific aspects of AD pathogenesis. We will argue that transgenic mice expressing amyloid precursor protein should be considered models of accelerated brain aging or asymptomatic AD, and the results of interventional studies in these mice should be considered in the context of primary prevention. Studies in mice have pointed to the roles of soluble beta-amyloid (Aβ) oligomers and soluble tau in disease pathogenesis and support a model in which soluble Aβ oligomers trigger synaptic dysfunction, but formation of abnormal tau species leads to neuron death and cognitive decline severe enough to warrant a dementia diagnosis. Alzheimer's disease (AD), the most common cause of dementia among the elderly, may either represent the far end of a continuum that begins with age-related memory decline or a distinct pathobiological process. Although mice that faithfully model all aspects of AD do not yet exist, current mouse models have provided valuable insights into specific aspects of AD pathogenesis. We will argue that transgenic mice expressing amyloid precursor protein should be considered models of accelerated brain aging or asymptomatic AD, and the results of interventional studies in these mice should be considered in the context of primary prevention. Studies in mice have pointed to the roles of soluble beta-amyloid (Aβ) oligomers and soluble tau in disease pathogenesis and support a model in which soluble Aβ oligomers trigger synaptic dysfunction, but formation of abnormal tau species leads to neuron death and cognitive decline severe enough to warrant a dementia diagnosis. Alzheimer's disease (AD) is the most common cause of dementia among the elderly. As life expectancy increases, the number of AD cases worldwide is expected to increase from 35 million today to more than 115 million by 2050 (http://www.alz.org/national/documents/report_full_2009worldalzheimerreport.pdf). The most effective approach to lessening the personal and financial costs of AD is to prevent the disease, but in order to develop prevention strategies, it is necessary to know when and how the disease begins. Molecular studies of the brain at the earliest stages of memory loss associated with AD have been difficult in humans. There is not even consensus among neurologists and neuroscientists as to whether AD is at the far end of a continuum that begins with age-related memory decline or whether AD is a distinct process. There are still no mice harboring a single Alzheimer's-linked gene variant that develop the progressive cognitive deficits, plaques, tangles, and neuronal loss characteristic of the human disease. Although there are not yet mice that faithfully model AD, existing mouse models have provided valuable insights into specific aspects of AD pathogenesis. The nosology of AD keeps shifting, the consequence of not knowing its etiology. This situation makes it difficult to place mouse models precisely into human context and demands an adaptive framework for utilizing mice as models of the human disease. Past and current criteria for a diagnosis of AD rely upon the presence at autopsy of characteristic neuropathological lesions, amyloid plaques formed from aggregated beta-amyloid protein (Aβ) and neurofibrillary tangles (NFTs) formed from abnormally processed tau protein. Recent advances in imaging technology now permit the observation of these lesions in living subjects and confirm the findings from neuropathological studies that up to 40% of nondemented older adults have sufficient amyloid deposition to meet neuropathological criteria for AD (Bennett et al., 2006Bennett D.A. Schneider J.A. Arvanitakis Z. Kelly J.F. Aggarwal N.T. Shah R.C. Wilson R.S. Neuropathology of older persons without cognitive impairment from two community-based studies.Neurology. 2006; 66: 1837-1844Crossref PubMed Scopus (480) Google Scholar, Hulette et al., 1998Hulette C.M. Welsh-Bohmer K.A. Murray M.G. Saunders A.M. Mash D.C. McIntyre L.M. Neuropathological and neuropsychological changes in “normal” aging: evidence for preclinical Alzheimer disease in cognitively normal individuals.J. Neuropathol. Exp. Neurol. 1998; 57: 1168-1174Crossref PubMed Google Scholar, Price et al., 2009Price J.L. McKeel Jr., D.W. Buckles V.D. Roe C.M. Xiong C. Grundman M. Hansen L.A. Petersen R.C. Parisi J.E. Dickson D.W. et al.Neuropathology of nondemented aging: presumptive evidence for preclinical Alzheimer disease.Neurobiol. Aging. 2009; 30: 1026-1036Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). The presence of substantial neuropathology in the brains of apparently normal individuals prompted the hypothesis that there is a long asymptomatic phase of AD, during which cognitive function is largely sustained in the presence of amyloid pathology (Price and Morris, 1999Price J.L. Morris J.C. Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease.Ann. Neurol. 1999; 45: 358-368Crossref PubMed Scopus (948) Google Scholar). Consistent with this hypothesis, a recent longitudinal study found that elevated cortical amyloid predicted decline in memory function (Storandt et al., 2009Storandt M. Mintun M.A. Head D. Morris J.C. Cognitive decline and brain volume loss as signatures of cerebral amyloid-beta peptide deposition identified with Pittsburgh compound B: cognitive decline associated with Abeta deposition.Arch. Neurol. 2009; 66: 1476-1481Crossref PubMed Scopus (156) Google Scholar) and the development of symptomatic AD (Morris et al., 2009Morris J.C. Roe C.M. Grant E.A. Head D. Storandt M. Goate A.M. Fagan A.M. Holtzman D.M. Mintun M.A. Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease.Arch. Neurol. 2009; 66: 1469-1475Crossref PubMed Scopus (259) Google Scholar) in elderly adults. Structural and functional neuroimaging studies provide further support for the existence of a prolonged asymptomatic phase in AD, which might precede the onset of clinical symptoms by decades. Individuals carrying mutations associated with familial autosomal-dominant AD are destined to develop symptoms at a predictable age for each family; abnormal patterns of brain activity and subtle cognitive deficits have been observed in mutation carriers more than 25 years before their expected conversion to dementia (Mondadori et al., 2006Mondadori C.R. Buchmann A. Mustovic H. Schmidt C.F. Boesiger P. Nitsch R.M. Hock C. Streffer J. Henke K. Enhanced brain activity may precede the diagnosis of Alzheimer's disease by 30 years.Brain. 2006; 129: 2908-2922Crossref PubMed Scopus (63) Google Scholar, Mosconi et al., 2006Mosconi L. Sorbi S. de Leon M.J. Li Y. Nacmias B. Myoung P.S. Tsui W. Ginestroni A. Bessi V. Fayyazz M. et al.Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease.J. Nucl. Med. 2006; 47: 1778-1786PubMed Google Scholar). Accelerated brain atrophy appears to follow functional changes, with regional differences between carriers and noncarriers apparent ∼5 years prior to the onset of clinical symptoms in the mutation carriers (Knight et al., 2009Knight W.D. Kim L.G. Douiri A. Frost C. Rossor M.N. Fox N.C. Acceleration of cortical thinning in familial Alzheimer's disease.Neurobiol. Aging. 2009; (in press. Published online December 14, 2009)https://doi.org/10.1016/j.neurobiolaging.2009.11.013Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, Ridha et al., 2006Ridha B.H. Barnes J. Bartlett J.W. Godbolt A. Pepple T. Rossor M.N. Fox N.C. Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study.Lancet Neurol. 2006; 5: 828-834Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). The ɛ4 allele of apolipoprotein E (APOE4) is the major genetic risk factor for sporadic Alzheimer's disease (Corder et al., 1993Corder E.H. Saunders A.M. Strittmatter W.J. Schmechel D.E. Gaskell P.C. Small G.W. Roses A.D. Haines J.L. Pericak-Vance M.A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science. 1993; 261: 921-923Crossref PubMed Google Scholar), and hypometabolism in brain regions affected in AD (de Leon et al., 1983de Leon M.J. Ferris S.H. George A.E. Christman D.R. Fowler J.S. Gentes C. Reisberg B. Gee B. Emmerich M. Yonekura Y. et al.Positron emission tomographic studies of aging and Alzheimer disease.AJNR Am. J. Neuroradiol. 1983; 4: 568-571PubMed Google Scholar, Kumar et al., 1991Kumar A. Schapiro M.B. Grady C. Haxby J.V. Wagner E. Salerno J.A. Friedland R.P. Rapoport S.I. High-resolution PET studies in Alzheimer's disease.Neuropsychopharmacology. 1991; 4: 35-46PubMed Google Scholar) has been observed in young adult (Reiman et al., 2004Reiman E.M. Chen K. Alexander G.E. Caselli R.J. Bandy D. Osborne D. Saunders A.M. Hardy J. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia.Proc. Natl. Acad. Sci. USA. 2004; 101: 284-289Crossref PubMed Scopus (472) Google Scholar) as well as middle-aged (Caselli et al., 2008Caselli R.J. Chen K. Lee W. Alexander G.E. Reiman E.M. Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment.Arch. Neurol. 2008; 65: 1231-1236Crossref PubMed Scopus (58) Google Scholar, Reiman et al., 1996Reiman E.M. Caselli R.J. Yun L.S. Chen K. Bandy D. Minoshima S. Thibodeau S.N. Osborne D. Preclinical evidence of Alzheimer's disease in persons homozygous for the epsilon 4 allele for apolipoprotein E.N. Engl. J. Med. 1996; 334: 752-758Crossref PubMed Scopus (926) Google Scholar, Reiman et al., 2001Reiman E.M. Caselli R.J. Chen K. Alexander G.E. Bandy D. Frost J. Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2001; 98: 3334-3339Crossref PubMed Scopus (317) Google Scholar) APOE4 carriers. In longitudinal studies, cognitively normal subjects exhibiting regional hypometabolism during baseline examinations were more likely to suffer future cognitive decline (de Leon et al., 2001de Leon M.J. Convit A. Wolf O.T. Tarshish C.Y. DeSanti S. Rusinek H. Tsui W. Kandil E. Scherer A.J. Roche A. et al.Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET).Proc. Natl. Acad. Sci. USA. 2001; 98: 10966-10971Crossref PubMed Scopus (424) Google Scholar, Small et al., 2000Small G.W. Ercoli L.M. Silverman D.H. Huang S.C. Komo S. Bookheimer S.Y. Lavretsky H. Miller K. Siddarth P. Rasgon N.L. et al.Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease.Proc. Natl. Acad. Sci. USA. 2000; 97: 6037-6042Crossref PubMed Scopus (508) Google Scholar) and to convert to AD (Mosconi et al., 2008Mosconi L. De Santi S. Li J. Tsui W.H. Li Y. Boppana M. Laska E. Rusinek H. de Leon M.J. Hippocampal hypometabolism predicts cognitive decline from normal aging.Neurobiol. Aging. 2008; 29: 676-692Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar) than were subjects with normal metabolic patterns. Volume loss in medial temporal regions in nondemented elderly individuals increases the risk for later conversion to mild cognitive impairment, considered by many to be a prodrome of AD (Petersen and Negash, 2008Petersen R.C. Negash S. Mild cognitive impairment: an overview.CNS Spectr. 2008; 13: 45-53Crossref PubMed Google Scholar), or to AD (de Toledo-Morrell et al., 2000de Toledo-Morrell L. Goncharova I. Dickerson B. Wilson R.S. Bennett D.A. From healthy aging to early Alzheimer's disease: in vivo detection of entorhinal cortex atrophy.Ann. N Y Acad. Sci. 2000; 911: 240-253Crossref PubMed Google Scholar, den Heijer et al., 2006den Heijer T. Geerlings M.I. Hoebeek F.E. Hofman A. Koudstaal P.J. Breteler M.M. Use of hippocampal and amygdalar volumes on magnetic resonance imaging to predict dementia in cognitively intact elderly people.Arch. Gen. Psychiatry. 2006; 63: 57-62Crossref PubMed Scopus (146) Google Scholar, Rusinek et al., 2003Rusinek H. De Santi S. Frid D. Tsui W.H. Tarshish C.Y. Convit A. de Leon M.J. Regional brain atrophy rate predicts future cognitive decline: 6-year longitudinal MR imaging study of normal aging.Radiology. 2003; 229: 691-696Crossref PubMed Scopus (166) Google Scholar). It is now possible to envision detecting AD long before the onset of clinical symptoms. An international consortium has attempted to identify AD at earlier stages using pathologically relevant biochemical, imaging, genetic, and neuropsychological tests (Dubois et al., 2007Dubois B. Feldman H.H. Jacova C. Dekosky S.T. Barberger-Gateau P. Cummings J. Delacourte A. Galasko D. Gauthier S. Jicha G. et al.Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria.Lancet Neurol. 2007; 6: 734-746Abstract Full Text Full Text PDF PubMed Scopus (1895) Google Scholar). However, the revised criteria are not yet ready for clinical use, because the proposed new biomarkers require further validation and are not available in most community clinical settings (Foster, 2007aFoster T.C. Calcium homeostasis and modulation of synaptic plasticity in the aged brain.Aging Cell. 2007; 6: 319-325Crossref PubMed Scopus (161) Google Scholar). Complicating our ability to define AD is the observation that amyloid plaques and NFTs coexist with other pathologies in 1/3–1/2 of patients with clinically diagnosed AD (Kovacs et al., 2008Kovacs G.G. Alafuzoff I. Al-Sarraj S. Arzberger T. Bogdanovic N. Capellari S. Ferrer I. Gelpi E. Kövari V. Kretzschmar H. et al.Mixed brain pathologies in dementia: the BrainNet Europe consortium experience.Dement. Geriatr. Cogn. Disord. 2008; 26: 343-350Crossref PubMed Scopus (69) Google Scholar, Schneider et al., 2009aSchneider J.A. Aggarwal N.T. Barnes L. Boyle P. Bennett D.A. The neuropathology of older persons with and without dementia from community versus clinic cohorts.J. Alzheimers Dis. 2009; 18: 691-701Crossref PubMed Scopus (104) Google Scholar, Schneider et al., 2009bSchneider J.A. Arvanitakis Z. Leurgans S.E. Bennett D.A. The neuropathology of probable Alzheimer disease and mild cognitive impairment.Ann. Neurol. 2009; 66: 200-208Crossref PubMed Scopus (279) Google Scholar). Infarcts are the most commonly occurring copathology in AD, and two theories have been proposed to explain the observed relationships between vascular pathology and AD: one posits an interaction between the pathogenic factors causing the two conditions (Korczyn, 2002Korczyn A.D. Mixed dementia—the most common cause of dementia.Ann. N Y Acad. Sci. 2002; 977: 129-134Crossref PubMed Google Scholar); the other that vascular pathology, specifically cerebral amyloid angiopathy and the physiological effects of Aβ on blood-flow regulation, constitutes an integral pathogenic feature of AD (Iadecola, 2004Iadecola C. Neurovascular regulation in the normal brain and in Alzheimer's disease.Nat. Rev. Neurosci. 2004; 5: 347-360Crossref PubMed Google Scholar). Additional copathologies include cortical Lewy bodies formed from aggregated α-synuclein (Schneider et al., 2007Schneider J.A. Arvanitakis Z. Bang W. Bennett D.A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons.Neurology. 2007; 69: 2197-2204Crossref PubMed Scopus (525) Google Scholar, Schneider et al., 2009aSchneider J.A. Aggarwal N.T. Barnes L. Boyle P. Bennett D.A. The neuropathology of older persons with and without dementia from community versus clinic cohorts.J. Alzheimers Dis. 2009; 18: 691-701Crossref PubMed Scopus (104) Google Scholar, Schneider et al., 2009bSchneider J.A. Arvanitakis Z. Leurgans S.E. Bennett D.A. The neuropathology of probable Alzheimer disease and mild cognitive impairment.Ann. Neurol. 2009; 66: 200-208Crossref PubMed Scopus (279) Google Scholar) and TDP-43-immunoreactive inclusions (Amador-Ortiz et al., 2007Amador-Ortiz C. Lin W.L. Ahmed Z. Personett D. Davies P. Duara R. Graff-Radford N.R. Hutton M.L. Dickson D.W. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease.Ann. Neurol. 2007; 61: 435-445Crossref PubMed Scopus (344) Google Scholar, Higashi et al., 2007Higashi S. Iseki E. Yamamoto R. Minegishi M. Hino H. Fujisawa K. Togo T. Katsuse O. Uchikado H. Furukawa Y. et al.Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer's disease and dementia with Lewy bodies.Brain Res. 2007; 1184: 284-294Crossref PubMed Scopus (153) Google Scholar, Josephs et al., 2008Josephs K.A. Whitwell J.L. Knopman D.S. Hu W.T. Stroh D.A. Baker M. Rademakers R. Boeve B.F. Parisi J.E. Smith G.E. et al.Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype.Neurology. 2008; 70: 1850-1857Crossref PubMed Scopus (87) Google Scholar, Kadokura et al., 2009Kadokura A. Yamazaki T. Lemere C.A. Takatama M. Okamoto K. Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: their relation to AD common pathology.Neuropathology. 2009; 29: 566-573Crossref PubMed Scopus (39) Google Scholar, Uryu et al., 2008Uryu K. Nakashima-Yasuda H. Forman M.S. Kwong L.K. Clark C.M. Grossman M. Miller B.L. Kretzschmar H.A. Lee V.M. Trojanowski J.Q. Neumann M. Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies.J. Neuropathol. Exp. Neurol. 2008; 67: 555-564Crossref PubMed Scopus (162) Google Scholar), characteristic neuropathological lesions of Parkinson's disease and ALS, respectively. It is not known whether the coexistence of these lesions with amyloid plaques and NFTs represents a pathological state that promotes protein misaggregation or the coincidental occurrence of independent pathological processes. Regardless of etiology, the likelihood of clinical dementia is significantly greater in persons who have mixed pathology than in individuals with plaques and NFTs alone (Langa et al., 2004Langa K.M. Foster N.L. Larson E.B. Mixed dementia: emerging concepts and therapeutic implications.JAMA. 2004; 292: 2901-2908Crossref PubMed Scopus (196) Google Scholar, Schneider et al., 2007Schneider J.A. Arvanitakis Z. Bang W. Bennett D.A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons.Neurology. 2007; 69: 2197-2204Crossref PubMed Scopus (525) Google Scholar, Schneider et al., 2009bSchneider J.A. Arvanitakis Z. Leurgans S.E. Bennett D.A. The neuropathology of probable Alzheimer disease and mild cognitive impairment.Ann. Neurol. 2009; 66: 200-208Crossref PubMed Scopus (279) Google Scholar, Snowdon et al., 1997Snowdon D.A. Greiner L.H. Mortimer J.A. Riley K.P. Greiner P.A. Markesbery W.R. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.JAMA. 1997; 277: 813-817Crossref PubMed Google Scholar). There is therefore concern that the effects of new Alzheimer therapies that are initially tested in mouse models and humans with pure AD may differ when they are dispensed to the general population. Pioneering investigations of amyloid plaques and neurofibrillary tangles led to the identification of the molecules comprising these lesions, the Aβ and tau proteins, respectively. Whether or not these lesions are themselves pathogenic, their presence reflects aberrant processing of Aβ and tau that leads to protein aggregation. Studies of the mechanisms of synapto- and neurotoxicity in transgenic mice have focused on toxic gains of function of these abnormal aggregates, although we cannot a priori exclude the possibility that loss of function of normal forms of these molecules also contributes to disease progression. Potential mechanisms of Aβ- and tau-induced toxicity will be discussed in “Physiological Basis of Memory Loss in Alzheimer Mouse Models” below. Aβ is generated from the proteolytic processing of the amyloid precursor protein (APP) by β- and γ-secretases (Figure 1). Genetic studies have revealed AD-linked mutations in APP and the presenilins, which form part of the γ-secretase complex (reviewed by Hardy, 2006Hardy J. A hundred years of Alzheimer's disease research.Neuron. 2006; 52: 3-13Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). Although not found in AD, mutations in tau are linked to another neurodegenerative disorder, frontotemporal dementia. Three scientific breakthroughs made possible the creation of the first transgenic mouse models of AD: (1) the isolation and sequencing of the Aβ peptide in 1984 (Glenner and Wong, 1984Glenner G.G. Wong C.W. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein.Biochem. 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These mutations appear to enhance the aggregation of Aβ, which occurs by one of four mechanisms. The Swedish mutation facilitating APP cleavage near the β-secretase site (Mullan et al., 1992Mullan M. Crawford F. Axelman K. Houlden H. Lilius L. Winblad B. Lannfelt L. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid.Nat. Genet. 1992; 1: 345-347Crossref PubMed Scopus (0) Google Scholar) increases the overall production of all forms of Aβ. A mutation within Aβ, called the Arctic mutation, enhances protofibril formation (Nilsberth et al., 2001Nilsberth C. Westlind-Danielsson A. Eckman C.B. Condron M.M. Axelman K. Forsell C. Stenh C. Luthman J. Teplow D.B. Younkin S.G. et al.The ‘Arctic’ APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation.Nat. Neurosci. 2001; 4: 887-893Crossref PubMed Scopus (573) Google Scholar). Several mutations near the γ-secretase site increase the relative production of the more amyloidogenic Aβ42 (Chartier-Harlin et al., 1991Chartier-Harlin M.-C. Crawford F. Houlden H. Warren A. Hughes D. Fidani L. Goate A. Rossor M. Roques P. Hardy J. Mullan M. Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene.Nature. 1991; 353: 844-846Crossref PubMed Google Scholar, Goate et al., 1991Goate A.M. Chartier-Harlin M.C. Mullan M. Brown J. Crawford F. Fidani L. Giuffra L. Haynes A. Irving N. James L. et al.Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.Nature. 1991; 349: 704-706Crossref PubMed Scopus (2001) Google Scholar, Murrell et al., 1991Murrell J. Farlow M. Ghetti B. Benson M.D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease.Science. 1991; 254: 97-99Crossref PubMed Google Scholar, Murrell et al., 2000Murrell J.R. Hake A.M. Quaid K.A. Farlow M.R. Ghetti B. Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene.Arch. Neurol. 2000; 57: 885-887Crossref PubMed Google Scholar). Duplications of the APP gene increase production of all forms of Aβ (Rovelet-Lecrux et al., 2006Rovelet-Lecrux A. Hannequin D. Raux G. Le Meur N. Laquerrière A. Vital A. Dumanchin C. Feuillette S. Brice A. Vercelletto M. et al.APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy.Nat. Genet. 2006; 38: 24-26Crossref PubMed Scopus (561) Google Scholar, Sleegers et al., 2006Sleegers K. Brouwers N. Gijselinck I. Theuns J. Goossens D. Wauters J. Del-Favero J. Cruts M. van Duijn C.M. Van Broeckhoven C. APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy.Brain. 2006; 129: 2977-2983Crossref PubMed Scopus (134) Google Scholar). Recently, an autosomal-recessive mutation involving the deletion of glutamate at Aβ residue 22 was found in a woman with dementia who apparently lacks amyloid plaques imaged with the amyloid binding agent Pittsburgh Compound B (Tomiyama et al., 2008Tomiyama T. Nagata T. Shimada H. Teraoka R. Fukushima A. Kanemitsu H. Takuma H. Kuwano R. Imagawa M. Ataka S. et al.A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia.Ann. Neurol. 2008; 63: 377-387Crossref PubMed Scopus (173) Google Scholar). This discovery raises the intriguing possibility that amyloid plaques may not be required to cause AD. Mutations in genes encoding the presenilins (∼80 mutations in presenilin-1 and ∼10 mutations in presenilin-2) cause the remaining cases of early-onset familial AD (http://www.alzforum.org/res/com/mut/pre/default.asp). Presenilin variants shift APP cleavage at the γ-secretase site, resulting in higher levels of the more amyloidogenic Aβ42 peptide. Familial AD caused by autosomal-dominant mutations in APP or the presenilins account for less than 10% of AD cases (Brouwers et al., 2008Brouwers N. Sleegers K. Van Broeckhoven C. Molecular genetics of Alzheimer's disease: an update.Ann. Med. 2008; 40: 562-583Crossref PubMed Scopus (113) Google Scholar, Cruts and Van Broeckhoven, 1998Cruts M. Van Broeckhoven C. Molecular genetics of Alzheimer's disease.Ann. Med. 1998; 30: 560-565Crossref PubMed Google Scholar), while the vast majority of cases arise sporadically. Aside from the earlier age of onset in familial AD cases, the neuropathological and cognitive abnormalities are generally similar in familial and sporadic AD (Lleó et al., 2004Lleó A. Berezovska O. Growdon J.H. Hyman B.T. Clinical, pathological, and biochemical spectrum of Alzheimer disease associated with PS-1 mutations.Am. J. Geriatr. Psychiatry. 2004; 12: 146-156Abstract Full Text Full Text PDF PubMed Google Scholar, Rossor et al., 1996Rossor M.N. Fox N.C. Freeborough P.A. Harvey R.J. Clinical features of sporadic and familial Alzheimer's disease.Neurodegeneration. 1996; 5: 393-397Crossref PubMed Scopus (13) Google Scholar, Swearer et al., 1992Swearer J.M. O'Donnell B.F. Drachman D.A. Woodward B.M. Neuropsychological features of familial Alzheimer's disease.Ann. Neurol. 1992; 32: 687-694Crossref PubMed Google Scholar). The view thus has emerged that pathological processing of APP, whether initiated by age-related factors or mutations, triggers the downstream processes that mediate disease progression (Hardy and Selkoe, 2002Hardy J. Selkoe D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.Science. 2002; 297: 353-356Crossref PubMed Scopus (6377) Google Scholar). Variants of tau (∼40 mutations) are linked to frontotemporal dementia (FTD), but no mutations in tau have been found in AD families (see http://www.molgen.ua.ac.be/ADMutations/default.cfm?MT=0&ML=1&Page=FTD for a regularly updated list of FTD-linked mutations). Mutations in APP or one of the presenilins are sufficient to cause the complete AD phenotype of progressive cognitive impairment, plaques, tangles, and neuron loss in the human brain. However, when expressed in mouse brain, human transgenes with these same mutations replicate some, but not all, aspects of AD. APP transgenic mice develop memory loss and plaques, with no NFTs and little or no neuron loss. Although APP transgenic mice fail to replicate the full human disease, they appear to faithfully simulate the predementia phase of AD. (A few dozen APP transgenic models have been published; a partial list can be found online at http://www.alzforum.org/res/com/tra/app/default.asp). Presenilin variants produce no neuropathology, but potentiate plaque deposition in APP transgenic mice. Despite the absence of linkage to AD, transgenic mice expressing human tau variants have been used to study neurofibrillary pathology, because, unlike in humans, the expression of APP and presenilin variants in mice is insufficient to induce neurofibrillary changes. In support of this approach, AD-related posttranslational modifications in tau, revealed" @default.
• W2054388625 created "2016-06-24" @default.
• W2054388625 creator A5011392349 @default.
• W2054388625 creator A5037038185 @default.
• W2054388625 date "2010-06-01" @default.
• W2054388625 modified "2023-10-14" @default.
• W2054388625 title "Probing the Biology of Alzheimer's Disease in Mice" @default.
• W2054388625 cites W1514559719 @default.
• W2054388625 cites W1518939040 @default.
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