Developmental patterns of neuronal thread protein gene expression in Down syndrome

Neuronal thread proteins (NTP) are a group of immunologically related molecules expressed in brain and neuroectodermal tumor cell lines. NTP gene expression is up-regulated and NTP molecules accumulate in Alzheimer's disease (AD) brains, pathological states associated with regenerative neuritic sprouting, and during brain development. To investigate the role of NTP over-expression in AD, we examined NTP immunoreactivity in brains from differently aged individuals with Down syndrome, since patients with Down syndrome nearly always develop AD neuropathology and dementia. Using SMI monoclonal antibodies to neurofilament protein, we detected age-associated increases in neurofilament immunoreactive (SMI-positive) neurites in Layers I and II of the cerebral cortex beginning at 1 year of age, followed by SMI-positive neurofibrillary tangles beginning at age 5 years, and then SMI-positive plaques beginning in the third decade. Increased NTP immunoreactivity in Down syndrome brains began in the second decade, prior to establishment of widespread AD neurodegeneration (Down syndrome + AD), and at an age when low-level or absent NTP expression was observed in control brains. Analysis of SDS and Triton X-100-treated histological sections and tissue extracts demonstrated that a largely insoluble, denaturation-resistant form of NTP accumulates in both Down syndrome + AD and AD brains. The findings provide further evidence that abnormal NTP expression and accumulation in brain may be an early marker of AD neurodegeneration in Down syndrome.