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Long-term basal forebrain cholinergic-rich grafts derived from trisomy 16 mice do not develop beta-amyloid pathology and neurodegeneration but demonstrate neuroinflammatory responses



Long-term basal forebrain cholinergic-rich grafts derived from trisomy 16 mice do not develop beta-amyloid pathology and neurodegeneration but demonstrate neuroinflammatory responses



International Journal of Developmental Neuroscience 16(7-8): 763-775



Patients with Down syndrome (human trisomy 21) develop neuropathological and cholinergic functional defects characteristic of Alzheimer's disease, which has been attributed to the location of the Alzheimer beta-amyloid precursor protein on chromosome 21. Due to the partial genetic homology between mouse chromosome 16 and human chromosome 21, murine trisomy 16 was used as a model to study functional links between increased expression of the amyloid precursor protein, neurodegeneration and neuroinflammatory responses. Basal forebrain cholinergic-rich tissue derived from trisomy 16 mice at embryonic age of day 16 was transplanted into the lateral ventricle of adult normal mice. At 1, 3, 6, 9 and 12 months after transplantation, the grafts were characterized by immunocytochemistry, molecular biological analysis, and stereological methods. Grafts survived up to one year and still demonstrated immunoreactivity for cholinergic, GABAergic and astroglial cells. Though a 1.5-fold neuronal over-expression of amyloid precursor protein was detected in brains from trisomy 16 embryos by Northern analysis, beta-amyloid deposits were found neither in control nor trisomic grafts. Detailed stereological analysis of trisomic grafts did not reveal any neurodegeneration or morphological changes of cholinergic and GABAergic neurons during the course of graft maturation up to one year, as compared to grafts derived from euploid tissue. However, both euploid and trisomic grafts demonstrated a strong infiltration with T- and B-lymphocytes and a significant micro- and astroglial activation (hypertrophic astrocytes) within and around the grafts. These observations further suggest that the trisomy 16-induced neurodegeneration is seemingly due to a lack of neuron supporting factors which are provided by either the metabolic interaction of trisomic graft with surrounding healthy host tissue or by cells of the immune system infiltrating the graft.

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Accession: 046567589

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PMID: 10198823


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