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

Patients with Down syndrome (human trisomy 21) develop neuropathological an d cholinergic functional defects characteristic of Alzheimer's disease, whi ch has been attributed to the location of the Alzheimer beta-amyloid precur sor protein on chromosome 21. Due to the partial genetic homology between m ouse chromosome 16 and human chromosome 21, murine trisomy 16 was used as a model to study functional links between increased expression of the amyloi d precursor protein, neurodegeneration and neuroinflammatory responses. Bas al forebrain cholinergic-rich tissue derived from trisomy 16 mice at embryo nic age of day 16 was transplanted into the lateral ventricle of adult norm al mice. At 1, 3, 6, 9 and 12 months after transplantation, the grafts were characterized by immunocytochemistry, molecular biological analysis, and s tereological methods. Grafts survived up to one year and still demonstrated immunoreactivity for cholinergic, GABAergic and astroglial cells. Though a 1.5-fold neuronal overexpression of amyloid precursor protein was detected in brains from trisomy 16 embryos by Northern analysis, beta-amyloid depos its were found neither in control nor trisomic grafts. Detailed stereologic al analysis of trisomic grafts did not reveal any neurodegeneration or morp hological changes of cholinergic and GABAergic neurons during the course of graft maturation up to one year, as compared to grafts derived from euploi d tissue. However, both euploid and trisomic grafts demonstrated a strong i nfiltration with T- and B-lymphocytes and a significant micro- and astrogli al 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 hea lthy host tissue or by cells of the immune system infiltrating the graft. ( C) 1999 ISDN. Published by Elsevier Science Ltd. All rights reserved.