neuropeptide-y and Down-Syndrome

Down syndrome, the leading genetic cause of intellectual disability, results from an extra-copy of chromosome 21. Mice engineered to model this aneuploidy exhibit Down syndrome-like memory deficits in spatial and contextual tasks. While abnormal neuronal function has been identified in these models, most studies have relied on

Topics: Action Potentials; Animals; CA1 Region, Hippocampal; Disease Models, Animal; Down Syndrome; Memory; Mice; Neuropeptide Y

We report on the autopsy of a 52-year-old Down's syndrome patient with a 9-year history of progressive dementia. Histologically, there was a marked neuronal loss in the cerebral cortices with numerous neurofibrillary tangles and senile plaques and congophilic angiopathy. The second cortical layer was spongy in appearance and the frontal and temporal white matter showed marked myelin pallor. Immunohistochemistry for MAP2 of the frontal and temporal cortices revealed great reduction in the number of large pyramidal neurons. On the other hand, a much stronger MAP2 immunoreactivity than that seen in the controls was observed in the second layer, which consisted of many small pyramidal neurons with features of aberrant sprouting. They were recognized in the frontal cortices but not in the temporal cortices, and were not immunolabeled with phosphorylated-tau nor MAP5. On double immunolabeling with MAP2 and beta-amyloid antibodies, these neurons were found to be not directly associated with the formation of senile plaques. Ultrastructurally, MAP2 was immunolocalized in an amorphous granular form in the neuronal somata and processes, and paired helical filaments were not immunolabeled. The observation may indicate the occurrence of a remarkable plastic response of small pyramidal cortical neurons in this patient with Down's syndrome.

Topics: Amyloid beta-Peptides; Cerebral Cortex; Down Syndrome; Female; Fluorescent Antibody Technique, Indirect; Humans; Immunohistochemistry; Microtubule-Associated Proteins; Middle Aged; Neurofibrillary Tangles; Neurons; Neuropeptide Y; Neuropil Threads; Parvalbumins; Phosphorylation; Plaque, Amyloid; Pyramidal Cells; tau Proteins

Neuropeptide Y (NPY)-containing neurons are depleted in the cortices of individuals with Alzheimer disease (AD), yet spared in the striatum of patients with Huntington chorea. It is unknown whether this neuronal phenotype is inherently susceptible to the neurodegenerative processes that are a hallmark of AD. To study this question, the murine trisomy 16 model of Down syndrome and Alzheimer disease was investigated. Since trisomic fetuses die in utero, studies were carried out on primary cultures of dissociated cortical neurons. These were prepared from 15-d gestational trisomy 16 fetuses and their littermate euploid controls, and examined by immunocytochemical staining for neuropeptide Y at 7 and 12 d in vitro. Trisomy 16 neurons were also grown on euploid glial carpets, whereas euploid neurons were grown on trisomic glia. The results demonstrate a significant increase in the number of NPY neurons and a stunting in the dendritic arbor of these neurons in trisomic vs euploid cortex. Both of these parameters could be normalized by direct contact with euploid glia. When euploid cortex was plated on trisomic glia, the number of NPY neurons and their morphology were altered so that they began to resemble trisomic NPY cortical neurons. These results indicate a dysregulation of NPY neuronal expression and differentiation in trisomy 16 cortex that are modifiable by interaction with euploid glia and imply an abnormal trophic (glial) environment in trisomic cortex.

Topics: Alzheimer Disease; Animals; Cell Differentiation; Cerebral Cortex; Disease Models, Animal; Down Syndrome; Female; Male; Mice; Mice, Inbred C57BL; Neuroglia; Neuronal Plasticity; Neurons; Neuropeptide Y; Trisomy