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Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease.

ABSTRACT: Galanin is a neuropeptide with multiple inhibitory actions on neurotransmission and memory. In Alzheimer's disease (AD), increased galanin-containing fibers hyperinnervate cholinergic neurons within the basal forebrain in association with a decline in cognition. We generated transgenic mice (GAL-tg) that overexpress galanin under the control of the dopamine beta-hydroxylase promoter to study the neurochemical and behavioral sequelae of a mouse model of galanin overexpression in AD. Overexpression of galanin was associated with a reduction in the number of identifiable neurons producing acetylcholine in the horizontal limb of the diagonal band. Behavioral phenotyping indicated that GAL-tgs displayed normal general health and sensory and motor abilities; however, GAL-tg mice showed selective performance deficits on the Morris spatial navigational task and the social transmission of food preference olfactory memory test. These results suggest that elevated expression of galanin contributes to the neurochemical and cognitive impairments characteristic of AD.

SUBMITTER: Steiner RA

PROVIDER: S-EPMC31200 | biostudies-literature | 2001 Mar

REPOSITORIES: biostudies-literature

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Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease.

Steiner R A RA Hohmann J G JG Holmes A A Wrenn C C CC Cadd G G Juréus A A Clifton D K DK Luo M M Gutshall M M Ma S Y SY Mufson E J EJ Crawley J N JN

Proceedings of the National Academy of Sciences of the United States of America 20010320 7

Galanin is a neuropeptide with multiple inhibitory actions on neurotransmission and memory. In Alzheimer's disease (AD), increased galanin-containing fibers hyperinnervate cholinergic neurons within the basal forebrain in association with a decline in cognition. We generated transgenic mice (GAL-tg) that overexpress galanin under the control of the dopamine beta-hydroxylase promoter to study the neurochemical and behavioral sequelae of a mouse model of galanin overexpression in AD. Overexpressio ...[more]

PMID: 11259657

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Project description:BACKGROUND:Amyloid ? (A?)-directed immunotherapy has shown promising results in preclinical and early clinical Alzheimer's disease (AD) trials, but successful translation to late clinics has failed so far. Compelling evidence suggests that post-translationally modified A? peptides might play a decisive role in onset and progression of AD and first clinical trials targeting such A? variants have been initiated. Modified A? represents a small fraction of deposited material in plaques compared to pan-A? epitopes, opening up pathways for tailored approaches of immunotherapy. Here, we generated the first monoclonal antibodies that recognize L-isoaspartate-modified A? (isoD7-A?) and tested a lead antibody molecule in 5xFAD mice. METHODS:This work comprises a combination of chemical and biochemical techniques as well as behavioral analyses. A? peptides, containing L-isoaspartate at position 7, were chemically synthesized and used for immunization of mice and antibody screening methods. Biochemical methods included anti-isoD7-A? monoclonal antibody characterization by surface plasmon resonance, immunohistochemical staining of human and transgenic mouse brain, and the development and application of isoD7-A? ELISA as well as different non-modified A? ELISA. For antibody treatment studies, 12?mg/kg anti-isoD7-A? antibody K11_IgG2a was applied intraperitoneally to 5xFAD mice for 38?weeks. Treatment controls implemented were IgG2a isotype as negative and 3D6_IgG2a, the parent molecule of bapineuzumab, as positive control antibodies. Behavioral studies included elevated plus maze, pole test, and Morris water maze. RESULTS:Our advanced antibody K11 showed a KD in the low nM range and?>?400fold selectivity for isoD7-A? compared to other A? variants. By using this antibody, we demonstrated that formation of isoD7-A? may occur after formation of aggregates; hence, the presence of the isoD7-modification differentiates aged A? from newly formed peptides. Importantly, we also show that the Tottori mutation responsible for early-onset AD in a Japanese pedigree is characterized by massively accelerated formation of isoD7-A? in cell culture. The presence of isoD7-A? was verified by K11 in post mortem human cortex and 5xFAD mouse brain tissue. Passive immunization of 5xFAD mice resulted in a significant reduction of isoD7-A? and total A? in brain. Amelioration of cognitive impairment was demonstrated by Morris water maze, elevated plus maze, pole, and contextual fear conditioning tests. Interestingly, despite the lower abundance of the isoD7-A? epitope, the application of anti-isoD7-A? antibodies showed comparable treatment efficacy in terms of reduction of brain amyloid and spatial learning but did not result in an increase of plasma A? concentration as observed with 3D6 treatment. CONCLUSIONS:The present study demonstrates, for the first time, that the antibody-mediated targeting of isoD7-modified A? peptides leads to attenuation of AD-like amyloid pathology. In conjunction with previously published data on antibodies directed against pGlu-modified A?, the results highlight the crucial role of modified A? peptides in AD pathophysiology. Hence, the results also underscore the therapeutic potential of targeting modified amyloid species for defining tailored approaches in AD therapy.

Project description:BackgroundSelective degeneration of medium spiny neurons and preservation of medium sized aspiny interneurons in striatum has been implicated in excitotoxicity and pathophysiology of Huntington's disease (HD). However, the molecular mechanism for the selective sparing of medium sized aspiny neurons and vulnerability of projection neurons is still elusive. The pathological characteristic of HD is an extensive reduction of the striatal mass, affecting caudate putamen. Somatostatin (SST) positive neurons are selectively spared in HD and Quinolinic acid/N-methyl-D-aspartic acid induced excitotoxicity, mimic the model of HD. SST plays neuroprotective role in excitotoxicity and the biological effects of SST are mediated by five somatostatin receptor subtypes (SSTR1-5).Methods and findingsTo delineate subtype selective biological responses we have here investigated changes in SSTR1 and 5 double knockout mice brain and compared with HD transgenic mouse model (R6/2). Our study revealed significant loss of dopamine and cAMP regulated phosphoprotein of 32 kDa (DARPP-32) and comparable changes in SST, N-methyl-D-aspartic acid receptors subtypes, calbindin and brain nitric oxide synthase expression as well as in key signaling proteins including calpain, phospho-extracellular-signal-regulated kinases1/2, synapsin-IIa, protein kinase C-? and calcineurin in SSTR1/5(-/-) and R6/2 mice. Conversely, the expression of somatostatin receptor subtypes, enkephalin and phosphatidylinositol 3-kinases were strain specific. SSTR1/5 appears to be important in regulating NMDARs, DARPP-32 and signaling molecules in similar fashion as seen in HD transgenic mice.ConclusionsThis is the first comprehensive description of disease related changes upon ablation of G- protein coupled receptor gene. Our results indicate that SST and SSTRs might play an important role in regulation of neurodegeneration and targeting this pathway can provide a novel insight in understanding the pathophysiology of Huntington's disease.

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Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease.

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Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease.

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