1 vs. 11.9 ± 3.4) (33) provides further proof that mental retardation is associated with increased levels of Aβ 42 in blood and gives clue that DMD mental retardation is associated with increased levels of Aβ 42. Previous studies have shown that individuals with DS have increased levels of Aβ40 and Aβ42 peptides in plasma together with increased risk for Alzheimer’s disease (AD), neuropathology and clinical dementia (34-38). In recent years there has been a substantial increase in the understanding of the role of dystrophin in the CNS. These studies have been largely carried out on DMD boys and the dystrophin EX 527 datasheet deficient mdx mouse and have demonstrated a range of

abnormalities in CNS function, from behavioral and cognitive dysfunction to alterations Inhibitors,research,lifescience,medical in the clustering of ion channels in single identified neurons (39). Dystrophin is considered the central component Inhibitors,research,lifescience,medical of a scaffold of proteins expressed in a variety of tissues

including the brain, where it is involved in the clustering of several membrane receptors and ion channels and in the modulation of cellular signal integration and synaptic plasticity (30). Normally, in the cerebellum, dystrophin appears to play Inhibitors,research,lifescience,medical a role in normal neuronal function or development. Two carboxy-terminal dystrophin proteins (Dp), Dp71 and Dp140, are both expressed in the brain, in addition to full-length central nervous system dystrophins, and are initiated between exons 62 and 63, and upstream from exon 44, respectively (40- 42). Rearrangements in the second part of the dystrophin

Inhibitors,research,lifescience,medical gene tend to be more commonly associated with cognitive impairment, and several reports described mutations in the Dp71 coding region as a factor that contributes to the severity of mental retardation (42-44). It is suggested that a lack of the Dp140 isoform is thought to play a significant role in cognitive performances in Duchenne muscular dystrophy (45, 46) and mutations involving the Dp71 region are often associated with severe cognitive impairment (47, 48). Putative alterations of the brain Inhibitors,research,lifescience,medical vascular permeability have been suggested by some studies, which may also participate to behavioral deficits in mdx mice (31). Initial observations of mdx brains revealed severe alterations of endothelial cells with open tight junctions surrounded by swollen glial processes and enhanced vascular permeability suggesting brain blood barrier (BBB) breakdown (48). Follow-up studies suggested that this results Histone demethylase partially from hypoxic condition leading to the activation of hypoxia inducible factor-1α contributing to both BBB opening and compensatory angiogenesis, along with changes in expression of matrix metalloproteinases, nerve and vascular growth factors (32). Hence, the hypothesis that a progressive decline in respiratory function due to muscle degeneration, could worsen the brain and cognitive impairments in advanced DMD patients through a reduction in cerebral oxygenation and BBB disruption (49).