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

Topic: Brain proteins, microglia and lab models

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.

Key findings

• Grafts survived up to one year and still demonstrated immunoreactivity for cholinergic, GABAergic and astroglial cells.
• 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.

Why it matters

In this mouse study, brain tissue grafts from trisomy 16 mice survived up to a year without developing beta-amyloid deposits or neurodegeneration, but both graft types showed neuroinflammatory responses. These are animal findings and do not establish any treatment, cure or prevention for Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/s0736-5748(98)00085-9
• PubMed: 10198823
• Original source →

May need a subscription OpenAlex found no free copy of the full text (checked 6 Feb 1020), so the publisher may charge for it. The PubMed abstract is free.

@article{stahl1998-10198823,
  author  = {Stahl, T. and Goldammer, A. and Luschekina, E. and Beck, M. and Schliebs, R. and Bigl, V.},
  title   = {{Long-term basal forebrain cholinergic-rich grafts derived from trisomy 16 mice do not develop beta-amyloid pathology and neurodegeneration but demonstrate neuroinflammatory responses}},
  journal = {International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience},
  year    = {1998},
  doi     = {10.1016/s0736-5748(98)00085-9},
  pmid    = {10198823},
  url     = {https://doi.org/10.1016/s0736-5748(98)00085-9}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• A mouse model for Down syndrome exhibits learning and behaviour deficits Nature genetics · 1995-10-01 · usefulness score 54/100 · Down syndrome and Alzheimer's
• The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases Brain research. Brain research reviews · 1995-09-01 · usefulness score 51/100 · Inflammation and the immune system
• Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome Proceedings of the National Academy of Sciences of the United States of America · 1996-11-01 · usefulness score 49/100 · Down syndrome and Alzheimer's
• Comparative mapping of DNA markers from the familial Alzheimer disease and Down syndrome regions of human chromosome 21 to mouse chromosomes 16 and 17 Proceedings of the National Academy of Sciences of the United States of America · 1988-08-01 · usefulness score 46/100 · Down syndrome and Alzheimer's
• Mouse model of neurodegeneration: atrophy of basal forebrain cholinergic neurons in trisomy 16 transplants Proceedings of the National Academy of Sciences of the United States of America · 1992-02-01 · usefulness score 38/100 · Down syndrome and Alzheimer's
• Glutamate as a hippocampal neuron survival factor: an inherited defect in the trisomy 16 mouse Proceedings of the National Academy of Sciences of the United States of America · 1995-10-01 · usefulness score 38/100 · Down syndrome and Alzheimer's
• Cerebral cortical astroglia from the trisomy 16 mouse, a model for down syndrome, produce neuronal cholinergic deficits in cell culture Proceedings of the National Academy of Sciences of the United States of America · 1997-11-01 · usefulness score 38/100 · Down syndrome and Alzheimer's
• Down syndrome Current opinion in neurology · 1997-04-01 · usefulness score 31/100 · Down syndrome and Alzheimer's
• Neuropeptide Y immunoreactive neurons in murine trisomy 16 cortical cultures. Plasticity of expression and differentiation Molecular and chemical neuropathology · 1994-08-01 · usefulness score 30/100 · Down syndrome and Alzheimer's

Later studies that cite this one

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• Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies Progress in neurobiology · 2002-10-01 · usefulness score 50/100 · Brain tissue and pathology

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