Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice
The cholinotrophic system, which is dependent upon nerve growth factor and its receptors for survival, is selectively vulnerable in Alzheimer's disease (AD). But, virtually nothing is known about how this deficit develops in relation to the hallmark lesions of this disease, amyloid plaques and...
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| Format: | Article |
| Language: | English |
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Elsevier
2011-02-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996110003335 |
| _version_ | 1818623747448373248 |
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| author | Sylvia E. Perez Bin He Nadeem Muhammad Kwang-Jin Oh Margaret Fahnestock Milos D. Ikonomovic Elliott J. Mufson |
| author_facet | Sylvia E. Perez Bin He Nadeem Muhammad Kwang-Jin Oh Margaret Fahnestock Milos D. Ikonomovic Elliott J. Mufson |
| author_sort | Sylvia E. Perez |
| collection | DOAJ |
| description | The cholinotrophic system, which is dependent upon nerve growth factor and its receptors for survival, is selectively vulnerable in Alzheimer's disease (AD). But, virtually nothing is known about how this deficit develops in relation to the hallmark lesions of this disease, amyloid plaques and tau containing neurofibrillary tangles. The vast majority of transgenic models of AD used to evaluate the effect of beta amyloid (Aβ) deposition upon the cholinotrophic system over-express the amyloid precursor protein (APP). However, nothing is known about how this system is affected in triple transgenic (3xTg)-AD mice, an AD animal model displaying Aβ plaque- and tangle-like pathology in the cortex and hippocampus, which receive extensive cholinergic innervation. We performed a detailed morphological and biochemical characterization of the cholinotrophic system in young (2–4 months), middle-aged (13–15 months) and old (18–20 months) 3xTg-AD mice. Cholinergic neuritic swellings increased in number and size with age, and were more conspicuous in the hippocampal–subicular complex in aged female than in 3xTg-AD male mice. Stereological analysis revealed a reduction in choline acetyltransferase (ChAT) positive cells in the medial septum/vertical limb of the diagonal band of Broca in aged 3xTg-AD mice. ChAT enzyme activity levels decreased significantly in the hippocampus of middle-aged 3xTg-AD mice compared to age-matched non-transgenic (or wild type) mice. ProNGF protein levels increased in the cortex of aged 3xTg-AD mice, whereas TrkA protein levels were reduced in a gender-dependent manner in aged mutant mice. In contrast, p75NTR protein cortical levels were stable but increased in the hippocampus of aged 3xTg-AD mice. These data demonstrate that cholinotrophic alterations in 3xTg-AD mice are age- and gender-dependent and more pronounced in the hippocampus, a structure more severely affected by Aβ plaque pathology. |
| first_indexed | 2024-12-16T18:45:59Z |
| format | Article |
| id | doaj.art-1a7a3f66f35043e6a1a6ef46f724f39d |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T18:45:59Z |
| publishDate | 2011-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-1a7a3f66f35043e6a1a6ef46f724f39d2022-12-21T22:20:50ZengElsevierNeurobiology of Disease1095-953X2011-02-01412338352Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic miceSylvia E. Perez0Bin He1Nadeem Muhammad2Kwang-Jin Oh3Margaret Fahnestock4Milos D. Ikonomovic5Elliott J. Mufson6Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, suite 300, Chicago, IL 60612, USADepartment of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, suite 300, Chicago, IL 60612, USADepartment of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, suite 300, Chicago, IL 60612, USADepartment of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, suite 300, Chicago, IL 60612, USADepartment of Psychiatry and Behavioral Neurosciences, McMaster University, 1200 Main Street W, Hamilton, ON, Canada L8N3Z5Departments of Neurology and Psychiatry, University of Pittsburgh School of Medicine, BSTWR S-521, 200 Lothrop Street, Pittsburgh, PA 15213-2536, USA; Geriatric Research Educational and Clinical Center, V.A. Pittsburgh Healthcare System, BSTWR S-521, 200 Lothrop Street, Pittsburgh, PA 15213-2536, USADepartment of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, suite 300, Chicago, IL 60612, USA; Corresponding author. Alla V. and Solomon Jesmer Chair in Aging, Rush University Medical Center, 1735 W. Harrison Street, Suite 300, Chicago, IL 60612, USA. Fax: +1 312 563 3571.The cholinotrophic system, which is dependent upon nerve growth factor and its receptors for survival, is selectively vulnerable in Alzheimer's disease (AD). But, virtually nothing is known about how this deficit develops in relation to the hallmark lesions of this disease, amyloid plaques and tau containing neurofibrillary tangles. The vast majority of transgenic models of AD used to evaluate the effect of beta amyloid (Aβ) deposition upon the cholinotrophic system over-express the amyloid precursor protein (APP). However, nothing is known about how this system is affected in triple transgenic (3xTg)-AD mice, an AD animal model displaying Aβ plaque- and tangle-like pathology in the cortex and hippocampus, which receive extensive cholinergic innervation. We performed a detailed morphological and biochemical characterization of the cholinotrophic system in young (2–4 months), middle-aged (13–15 months) and old (18–20 months) 3xTg-AD mice. Cholinergic neuritic swellings increased in number and size with age, and were more conspicuous in the hippocampal–subicular complex in aged female than in 3xTg-AD male mice. Stereological analysis revealed a reduction in choline acetyltransferase (ChAT) positive cells in the medial septum/vertical limb of the diagonal band of Broca in aged 3xTg-AD mice. ChAT enzyme activity levels decreased significantly in the hippocampus of middle-aged 3xTg-AD mice compared to age-matched non-transgenic (or wild type) mice. ProNGF protein levels increased in the cortex of aged 3xTg-AD mice, whereas TrkA protein levels were reduced in a gender-dependent manner in aged mutant mice. In contrast, p75NTR protein cortical levels were stable but increased in the hippocampus of aged 3xTg-AD mice. These data demonstrate that cholinotrophic alterations in 3xTg-AD mice are age- and gender-dependent and more pronounced in the hippocampus, a structure more severely affected by Aβ plaque pathology.http://www.sciencedirect.com/science/article/pii/S0969996110003335Alzheimer's diseaseAmyloidCholinergicNerve growth factorChATproNGF |
| spellingShingle | Sylvia E. Perez Bin He Nadeem Muhammad Kwang-Jin Oh Margaret Fahnestock Milos D. Ikonomovic Elliott J. Mufson Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice Neurobiology of Disease Alzheimer's disease Amyloid Cholinergic Nerve growth factor ChAT proNGF |
| title | Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice |
| title_full | Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice |
| title_fullStr | Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice |
| title_full_unstemmed | Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice |
| title_short | Cholinotrophic basal forebrain system alterations in 3xTg-AD transgenic mice |
| title_sort | cholinotrophic basal forebrain system alterations in 3xtg ad transgenic mice |
| topic | Alzheimer's disease Amyloid Cholinergic Nerve growth factor ChAT proNGF |
| url | http://www.sciencedirect.com/science/article/pii/S0969996110003335 |
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