Skeletal muscle is not the sole non neural tissue in which mitochondrial abnormalities are associated with AD. Mitochondrial abnormalities are already very well docu mented in cybrid programs the place platelets containing mitochondria from AD patients are fused to immortal ized cells in culture. Regardless of whether such abnormalities are widespread amongst tissues is unclear given that mito chondrial function in lymphocytes of AD patients has been reported to get normal. Recent studies have also demonstrated mitochondrial abnormalities in transgenic AD murine designs that more than express human amyloid precursor protein both in cells and isolated mitochondria. Principal neuronal cultures isolated from Tg2576 mice, a well characterized APP murine model of AD had decreased synaptic proteins and deficits in axonal transport of mito chondria.

These deficiencies correlated temporally with accumulation of oligomeric beta amyloid. Making use of isolated brain mitochondria from three month old mice pos sessing two human APP mutations demonstrate decreased mitochondrial membrane likely and decreased ATP ranges that corre lated temporally with intracellular selleckchem beta amyloid. With each other, these scientific studies suggest that mitochondrial dys function precedes extracellular amyloid deposition. AD transgenic mice such as the very well studied strain possessing each a chimeric mouse human amyloid precur sor protein together with the Swedish mutations in addition to a mutant type of presenilin 1 with deletion of exon 9 appears to express APP not only in brain, but in muscle also.

Consequently, we hypothesized that overexpres sion of an AD form of APP, could result in mitochondrial selleck abnormalities in both tissue forms, and testing of this hy pothesis could support elucidate the relationship of muscle and cognitive deficits in AD. Furthermore, we examined the hypothesis that mitochondrial dysfunction is surely an early occasion that might exacerbate amyloid toxicity predisposing vulnerable neuronal and non neuronal cell populations to degenerate. We now show in this double transgenic mouse strain that skeletal muscle tissue have differential amounts of mu tant total length APP based upon muscle sort. Isolated muscle fibers from young mice have signifi cantly decreased maximal oxygen consumption capability when compared to non transgenic, age matched mice, with simi lar mitochondrial deficits to these previously described in brain. This is actually the to start with study to right examine mitochon drial perform in skeletal muscle from an AD pertinent transgenic murine model. As with brain, these deficits in muscle are an early occasion, taking place just before appearance of amyloid plaques.