Progress toward valid transgenic mouse models for Alzheimer's disease.
A transgenic mouse model for Alzheimer's disease (AD) should mimic the age-dependent accumulation of beta-amyloid plaques, neurofibrillary tangles, neuronal cell death as well as display memory loss and behavioral deficits. Age-dependent accumulation of A beta deposits in mouse brain has been achieved in mice overexpressing mutant alleles of the amyloid precursor protein (APP). In contrast, mice bearing mutant alleles of the presenilin genes show increased production of the A beta42 peptide, but do not form amyloid deposits unless mutant alleles of APP are also overproduced. Furthermore, the onset of A beta deposition is greatly accelerated, paralleling the involvement of presenilins in early onset AD. Studies of APP and presenilin transgenic mice have shown 1) the absence of a requirement for a maturation step in dense core plaque formation, 2) evidence that beta-amyloid deposition is directed by regional factors, and 3) behavioral deficits are observed before A beta deposition. Crosses of APP transgenic mice with mice modified for known AD risk factors and "humanizing" the mouse may be necessary for complete replication of AD.
Guénette
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Department of Neurology, Massachusetts General Hospital, Charlestown 02129, USA. guenette@helix.mgh.harvard.edu
Tanzi
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D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005911:Gliosis / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008569:Memory Disorders / Q000175:diagnosis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D016501:Neurites / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics; D053764:Presenilin-1; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; C092826:amyloid precursor protein, carboxy-terminal 100 residues; D016875:tau Proteins