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Alzheimer mice on the couch
Neurobiology of Aging 21 (2000) 873
www.elsevier.com/locate/neuaging
Commentary
Alzheimer mice on the couch Sam Gandy* Department of Psychiatry New York University School of Medicine, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg NY 10962 Received 5 June 2000; accepted 27 June 2000
Cummings raises the interesting possibility that transgenic models of Alzheimer-type cerebral amyloidosis (or, now that they have been successfully developed, models of Alzheimer-type neurofibrillary pathology) might be useful for elucidating the structural bases for the behavioral and mood changes that can be associated with Alzheimer disease (AD) in humans. This seems like a perfectly valid proposal, which can and should be evaluated experimentally. It is easy to see why this idea is late in coming to the table: the development of these animals has largely been the work of molecular biologists working in collaboration with neuropathologists. Unlike the functional brain disorders, AD is defined by prominent structural pathology (N.B., there is an echo here of the traditional-and increasingly artificial-boundary separating neurology and psychiatry). Because of the focus on structural pathology, major goals in this area focussed on creating plaques and tangles which mimicked their human counterparts at both the neuroanatomic and molecular levels. Cognitive assessment of these animals was rather long in coming and has been ultimately disappointing [1]. It seems certain that the failure of plaqueforming mice to demonstrate obvious cognitive failure deflated efforts which might have gone in the directions which Cummings suggests: plaque-forming mice develop striking— but apparently mostly benign— cerebral amyloidosis and lack a cardinal feature of AD: dementia [1]. Another reason for the under-investigation of mood and behavior in plaque-forming mice is, of course, the race to identify safe, effective anti-amyloid compounds. Hundreds of thousands of compounds have been put through various types of anti-amyloid screening assays, and testing their efficacy in plaque-forming mice is the make-or-break step determining which might go on to human clinical trials and which are investigated no further. Are the experiments proposed by Cummings likely to yield important information? One can never predict this, of course, but it seems likely. For example, this direction * Corresponding author. Tel. 001-914-398-5431; fax: 001-914-398-5422. E-mail address: [email protected] (S. Gandy).
would stimulate the development and refinement of functional and structural brain imaging techniques to make them routinely applicable to mice. Such capability is sorely needed, and that need will only grow as more “interesting” mice with chemical or structural brain pathology are created. Are plaque-forming mice depressed? Certainly not to the point of profound psychomotor retardation but subtler changes cannot be excluded without specific behavioral assays such as those used in testing psychopharmaceuticals. It is worth noting that neophobia was one of the first amyloid-transgene-related phenotypes [2], but its structural and functional bases have not been elucidated. As transgenic models now produce “anxious” mice [3], it is perfectly appropriate to reflect upon other models already in hand and wonder whether they, too, might have something to contribute to our understanding of the structural and functional basis of brain diseases which are characterized by both “neurological” and “psychiatric” manifestations. While this commentary was in press, a review appeared (Bolivar V, Cook M, Flaherty L. List of transgenic and knockout mice: behavioral profiles. Mamm Genome. 2000; 11(4):260 –74) which summarizes the existing literature on the behavioral phenotypes of genetically modified mice. Several Alzheimer-type plaque-forming transgenic mouse lines are included in this summary, and, when taken in the context of the numerous behavioral tests available for studying mutant mice, the relative infrequency with which this battery has been applied to Alzheimer plaque-forming mice is readily apparent. Thus, Bolivar et al provide strong support for Cummings’ position. References [1] Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D. Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet 1999;29(3):177– 85. [2] Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, Xu S, Eckman C, Younkin S, Price D. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 1995;15(5):1203–18. [3] Tecott LH. Designer genes and anti-anxiety drugs. Nat Neurosci 2000;3(6):529 –30.
0197-4580/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S - 1 9 7 - 4 5 8 0 ( 0 0 ) 0 0 1 8 8 - 3
www.elsevier.com/locate/neuaging
Commentary
Alzheimer mice on the couch Sam Gandy* Department of Psychiatry New York University School of Medicine, The Nathan S. Kline Institute for Psychiatric Research, Orangeburg NY 10962 Received 5 June 2000; accepted 27 June 2000
Cummings raises the interesting possibility that transgenic models of Alzheimer-type cerebral amyloidosis (or, now that they have been successfully developed, models of Alzheimer-type neurofibrillary pathology) might be useful for elucidating the structural bases for the behavioral and mood changes that can be associated with Alzheimer disease (AD) in humans. This seems like a perfectly valid proposal, which can and should be evaluated experimentally. It is easy to see why this idea is late in coming to the table: the development of these animals has largely been the work of molecular biologists working in collaboration with neuropathologists. Unlike the functional brain disorders, AD is defined by prominent structural pathology (N.B., there is an echo here of the traditional-and increasingly artificial-boundary separating neurology and psychiatry). Because of the focus on structural pathology, major goals in this area focussed on creating plaques and tangles which mimicked their human counterparts at both the neuroanatomic and molecular levels. Cognitive assessment of these animals was rather long in coming and has been ultimately disappointing [1]. It seems certain that the failure of plaqueforming mice to demonstrate obvious cognitive failure deflated efforts which might have gone in the directions which Cummings suggests: plaque-forming mice develop striking— but apparently mostly benign— cerebral amyloidosis and lack a cardinal feature of AD: dementia [1]. Another reason for the under-investigation of mood and behavior in plaque-forming mice is, of course, the race to identify safe, effective anti-amyloid compounds. Hundreds of thousands of compounds have been put through various types of anti-amyloid screening assays, and testing their efficacy in plaque-forming mice is the make-or-break step determining which might go on to human clinical trials and which are investigated no further. Are the experiments proposed by Cummings likely to yield important information? One can never predict this, of course, but it seems likely. For example, this direction * Corresponding author. Tel. 001-914-398-5431; fax: 001-914-398-5422. E-mail address: [email protected] (S. Gandy).
would stimulate the development and refinement of functional and structural brain imaging techniques to make them routinely applicable to mice. Such capability is sorely needed, and that need will only grow as more “interesting” mice with chemical or structural brain pathology are created. Are plaque-forming mice depressed? Certainly not to the point of profound psychomotor retardation but subtler changes cannot be excluded without specific behavioral assays such as those used in testing psychopharmaceuticals. It is worth noting that neophobia was one of the first amyloid-transgene-related phenotypes [2], but its structural and functional bases have not been elucidated. As transgenic models now produce “anxious” mice [3], it is perfectly appropriate to reflect upon other models already in hand and wonder whether they, too, might have something to contribute to our understanding of the structural and functional basis of brain diseases which are characterized by both “neurological” and “psychiatric” manifestations. While this commentary was in press, a review appeared (Bolivar V, Cook M, Flaherty L. List of transgenic and knockout mice: behavioral profiles. Mamm Genome. 2000; 11(4):260 –74) which summarizes the existing literature on the behavioral phenotypes of genetically modified mice. Several Alzheimer-type plaque-forming transgenic mouse lines are included in this summary, and, when taken in the context of the numerous behavioral tests available for studying mutant mice, the relative infrequency with which this battery has been applied to Alzheimer plaque-forming mice is readily apparent. Thus, Bolivar et al provide strong support for Cummings’ position. References [1] Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D. Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet 1999;29(3):177– 85. [2] Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, Xu S, Eckman C, Younkin S, Price D. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron 1995;15(5):1203–18. [3] Tecott LH. Designer genes and anti-anxiety drugs. Nat Neurosci 2000;3(6):529 –30.
0197-4580/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S - 1 9 7 - 4 5 8 0 ( 0 0 ) 0 0 1 8 8 - 3