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Of mice and men: The relevance of transgenic mice Aβ immunizations to Alzheimer's disease

Published on Nov 1, 2002in Journal of Alzheimer's Disease 3.70
· DOI :10.3233/JAD-2002-4509
Alex E. Roher57
Estimated H-index: 57
,
Tyler A. Kokjohn29
Estimated H-index: 29
Cite
Abstract
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by a time-dependent amyloid fibril deposition in cortical senile plaques and cerebral vascular walls. Several transgenic (Tg) mice have been engineered to overexpress amyloid-beta precursor protein (AβPP) with familial AD mutations. With advancing age, the Tg mice accumulate amyloidbeta (Aβ) peptides, primarily of 40 to 42 amino acids, in plaques and blood vessel wall deposits which resemble morphologically those characteristic of AD. Immunizing Tg mice with Aβ peptides or infusion of antiAβ antibodies resulted in a remarkable Aβ load decrease and reversal of cognitive dysfunction in these animals [1–4]. These observations led to immediate efforts to employ similar therapeutic protocols in AD patients. However, Tg hAβPP-overexpressing mice differ from AD patients in several important biochemical, anatomical, pathological and temporal aspects. These fundamental differences must be considered when extrapolating Tg mice Aβ vaccination experimental observations to AD. It is now clear that the amyloid deposits of Tg mice chemically characterized to date are not necessarily
  • References (21)
  • Citations (10)
Cite
References21
Newest
Published on Jan 1, 2002in Biochemistry 2.95
Walter M. Kalback20
Estimated H-index: 20
,
M. Desiree Watson7
Estimated H-index: 7
+ 9 AuthorsMatthias Staufenbiel77
Estimated H-index: 77
The amyloid (Aβ) peptides generated in Hsiao's APP Tg2576 transgenic (Tg) mice are physically and chemically distinct from those characteristic of Alzheimer's disease (AD). Transgenic mouse Aβ peptides were purified using sequential size-exclusion and reverse-phase chromatographic systems and subjected to amino acid sequencing and mass spectrometry analyses. The mouse Aβ peptides lacked the extensive N-terminal degradations, posttranslational modifications, and cross-linkages abundant in the sta...
Published on Sep 1, 2001in Neurobiology of Aging 4.40
Pritam Das36
Estimated H-index: 36
(Mayo Clinic),
M. Paul Murphy10
Estimated H-index: 10
(Mayo Clinic)
+ 2 AuthorsTodd E. Golde68
Estimated H-index: 68
(Mayo Clinic)
Abstract Vaccinations with Aβ1-42 have been shown to reduce amyloid burden in transgenic models of Alzheimer’s disease (AD). We have further tested the efficacy of Aβ1-42 immunization in the Tg2576 mouse model of AD by immunizing one group of mice with minimal Aβ deposition, one group of mice with modest Aβ deposition, and one group with significant Aβ deposition. The effects of immunization on Aβ deposition were examined using biochemical and immunohistochemical methods. In Tg2576 mice immunize...
Published on Aug 1, 2001in Physiology & Behavior 2.63
Christopher Janus16
Estimated H-index: 16
(U of T: University of Toronto),
David Westaway47
Estimated H-index: 47
(U of T: University of Toronto)
Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by a progressive loss of cognitive function. Despite considerable progress, a complete description of the molecular pathology of this disease has yet to be elucidated. In this respect, the need for an animal model that develops some or all aspects of this uniquely human disease in a reproducible fashion is crucial for the development and testing of potential treatments. A valid animal model for AD should exhibit (1) progress...
Published on Apr 20, 2001in Journal of Biological Chemistry
Yu-Min Kuo2
Estimated H-index: 2
(ASU: Arizona State University),
Tyler A. Kokjohn2
Estimated H-index: 2
(ASU: Arizona State University)
+ 8 AuthorsMatthias Staufenbiel1
Estimated H-index: 1
(ASU: Arizona State University)
Abstract We have undertaken an integrated chemical and morphological comparison of the amyloid-β (Aβ) molecules and the amyloid plaques present in the brains of APP23 transgenic (tg) mice and human Alzheimer's disease (AD) patients. Despite an apparent overall structural resemblance to AD pathology, our detailed chemical analyses revealed that although the amyloid plaques characteristic of AD contain cores that are highly resistant to chemical and physical disruption, the tg mice produced amyloi...
Published on Mar 1, 2001in Nature Medicine 30.64
Brian J. Bacskai67
Estimated H-index: 67
(Harvard University),
Stephen T. Kajdasz11
Estimated H-index: 11
(Harvard University)
+ 5 AuthorsBradley T. Hyman148
Estimated H-index: 148
(Harvard University)
Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy
Published on Jan 1, 2001in Nature Medicine 30.64
Steve Younkin78
Estimated H-index: 78
Studies in three different transgenic mouse models suggest that the amyloid β-protein contributes to memory loss in Alzheimer disease. Immunization with an amyloid β-peptide fragment reduces learning and memory impairments in mice, and this approach may eventually be used to prevent and/or treat this disease in people.
Published on Aug 1, 2000in Nature Medicine 30.64
Frederique Bard17
Estimated H-index: 17
,
Catherine Cannon7
Estimated H-index: 7
+ 20 AuthorsKelly Johnson-Wood21
Estimated H-index: 21
Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease
Published on May 1, 2000in Molecular Medicine 2.99
Yu-Min Kuo44
Estimated H-index: 44
,
Fiona Crawford45
Estimated H-index: 45
(USF: University of South Florida)
+ 4 AuthorsAlex E. Roher57
Estimated H-index: 57
Background: Amyloid-� (A� ) accumulates in plaques and as cerebral amyloid angiopathy (CAA) in the brains of both Alzheimer's disease (AD) pa- tients and transgenic APPswe/tg2576 (tg2576) mice. Increasingly, evidence in humans and mice shows this process to be modulated by apolipopro- tein E (apoE). Materia fls and Methods: To explore this relation- ship, we measured apoE and Alevels in brains of tg2576 mice and controls at intervals between 2 and 20 months. In addition, Aconcentrations in plasm...
Published on Jan 1, 2000
Alex E. Roher57
Estimated H-index: 57
,
Yu-Min Kuo3
Estimated H-index: 3
+ 2 AuthorsWarren J. Goux15
Estimated H-index: 15
(UTD: University of Texas at Dallas)
Substantial evidence demonstrates that amyloid deposition in the cerebral vasculature plays a major role in the pathophysiology of Alzheimer’s disease. Chemical and immunohistochemical analyses have demonstrated that Aβ40 and Aβ42 peptides are present in vascular amyloid deposits with a preponderance of the former peptide. The accumulation of cerebrovascular amyloid leads to obliteration of capillary lumen and destruction arterial myocytes resulting in hypoperfusion and loss of control of cerebr...
Published on Nov 5, 1999in Journal of Biological Chemistry
Haeyong Chung2
Estimated H-index: 2
(Columbia University),
Melanie I. Brazil1
Estimated H-index: 1
(Columbia University)
+ 1 AuthorsFrederick R. Maxfield84
Estimated H-index: 84
(Columbia University)
Abstract Microglia are phagocytic cells that are the main inflammatory response cells of the central nervous system. In Alzheimer's disease brain, activated microglia are concentrated in regions of compact amyloid deposits that contain the 39–43-amino acid Aβ peptide. We examined the uptake, degradation, and release of small aggregates of fibrillar Aβ (fAβ) or soluble Aβ (sAβ) by microglia. We found that although some degradation of fAβ was observed over 3 days, no further degradation was observ...
Cited By10
Newest
Published on Jan 1, 2017
Akhlaq A. Farooqui46
Estimated H-index: 46
(OSU: Ohio State University)
Both active and passive anti-β-amyloid (Aβ) immunotherapies have been reported to clear brain Aβ deposits in transgenic mouse models of Alzheimer's disease (AD). These studies have also indicated that anti-Aβ immunotherapy not only reduces cerebral Aβ burden in the brain but also causes a reduction in cognitive decline. However, results in transgenic mice do not translate well in humans. AN1792 is a vaccine that is composed of preaggregated Aβ1-42 and QS21 as an adjuvant. This vaccine has been d...
Published on Jan 1, 2013in Frontiers in Pharmacology 3.85
Claudia Saraceno6
Estimated H-index: 6
,
Stefano Musardo7
Estimated H-index: 7
(University of Milan)
+ 2 AuthorsM. DiLuca52
Estimated H-index: 52
(University of Milan)
Alzheimer’s disease (AD) is emerging as the most prevalent and socially disruptive illness of aging populations, as more people live long enough to become affected. Although AD is placing a considerable and increasing burden on society, it represents the largest unmet medical need in neurology, because current drugs improve symptoms, but do not have profound disease-modifying effects. Although AD pathogenesis is multifaceted and difficult to pinpoint, genetic and cell biological studies led to t...
Published on Jun 1, 2011in Neuromolecular Medicine 2.58
Claudia Balducci22
Estimated H-index: 22
(Mario Negri Institute for Pharmacological Research),
Gianluigi Forloni58
Estimated H-index: 58
(Mario Negri Institute for Pharmacological Research)
Alzheimer’s disease is the most widespread form of dementia. Its histopathological hallmarks include vascular and extracellular β-amyloid (Aβ) deposition and intraneuronal neurofibrillary tangles (NFTs). Gradual decline of cognitive functions linked to progressive synaptic loss makes patients unable to store new information in the earlier stages of the pathology, later becoming completely dependent because they are unable to do even elementary daily life actions. Although more than a hundred yea...
Published on Oct 1, 2010in Neuropathology and Applied Neurobiology 6.88
Nienke Timmer6
Estimated H-index: 6
(Radboud University Nijmegen Medical Centre),
Megan K. Herbert11
Estimated H-index: 11
(Radboud University Nijmegen Medical Centre)
+ 3 AuthorsMarcel M. Verbeek56
Estimated H-index: 56
(Radboud University Nijmegen Medical Centre)
N. M. Timmer, M. K. Herbert, J. W. Kleinovink, A. J. Kiliaan, R. M. W. de Waal and M. M. Verbeek (2010) Neuropathology and Applied Neurobiology36, 478–486 Limited expression of heparan sulphate proteoglycans associated with Aβ deposits in the APPswe/PS1dE9 mouse model for Alzheimer's disease Aims: Alzheimer's disease (AD) is characterized by deposition of the amyloid beta (Aβ) peptide in brain parenchyma and vasculature. Several proteins co-deposit with Aβ, including heparan sulphate proteoglyca...
Published on Jan 1, 2010in Mount Sinai Journal of Medicine
Thomas Wisniewski69
Estimated H-index: 69
,
Allal Boutajangout16
Estimated H-index: 16
(NYU: New York University)
Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high β-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid β peptide is converted into oligomeric/fibrillar amyloid β. The oligomeric forms of amyloid β have been hypothesized to be the...
Published on Jul 1, 2009in Alzheimers & Dementia 14.42
Tyler A. Kokjohn29
Estimated H-index: 29
(MWU: Midwestern University),
Alex E. Roher57
Estimated H-index: 57
Abstract Transgenic (Tg) mice that overexpress mutant familial Alzheimer's disease (AD) amyloid precursor protein (APP) genes have contributed to an understanding of dementia pathology, and support the amyloid cascade hypothesis. Although many sophisticated mice APP models exist, none recapitulates AD cellular and behavioral pathology. The morphological resemblance to AD amyloidosis is impressive, but fundamental biophysical and biochemical properties of the APP/Aβ produced in Tg mice differ sub...
Published on Apr 1, 2009in Cns & Neurological Disorders-drug Targets 2.76
Tyler A. Kokjohn29
Estimated H-index: 29
,
Alex E. Roher57
Estimated H-index: 57
Post mortem examinations of AN-1792-vaccinated humans revealed this therapy produced focal senile plaque disruption. Despite the dispersal of substantial plaque material, vaccination did not constitute even a partial eradication of brain amyloid as water soluble amyloid-β (Aβ) 40/42 increased in the gray matter compared to sporadic Alzheimer's disease (AD) patients and total brain Aβ levels were not decreased. Significant aspects of AD pathology were unaffected by vaccination with both vascular ...
Published on Jan 1, 2009
Tyler A. Kokjohn29
Estimated H-index: 29
,
Alex E. Roher6
Estimated H-index: 6
Transgenic (Tg) mice that overexpress mutant familial Alzheimer’s disease (AD) amyloid precursor protein (APP) genes have contributed to an understanding of dementia pathology, and support the amyloid cascade hypothesis. Although many sophisticated mice APP models exist, none recapitulates AD cellular and behavioral pathology. The morphological resemblance to AD amyloidosis is impressive, but fundamental biophysical and biochemical properties of the APP/Ab produced in Tg mice differ substantiall...
Published on Jan 1, 2004in Brain Pathology 6.16
Isidre Ferrer72
Estimated H-index: 72
(University of Barcelona),
Mercé Boada Rovira1
Estimated H-index: 1
+ 2 AuthorsFrederic Costa-Jussá1
Estimated H-index: 1
Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop β-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non treated transgenic animals im-munization with amyloid β peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examin...