New Target For Alzheimer's Disease Therapy

This report can be found in the April 2009 issue of The American Journal of Pathology.

Alzheimer's disease is an incurable, degenerative, terminal form of dementia, thought to be caused in part by the presence of "tangles" of misfolded proteins. The unfolded protein response protects cells from the toxic effects of accumulated misfolded proteins; however, prolonged activation of the unfolded protein response, such as in Alzheimer's disease, may lead to cell death.

Hoozemans et al hypothesized that the unfolded protein response contributed to neurodegeneration in Alzheimer's disease partially though its effects on the accumulation of hyperphosphorylated tau, a major component of tangles in Alzheimer's disease patients. They found that markers of the unfolded protein response were expressed in areas of tau accumulation in patients with Alzheimer's disease. These unfolded protein response-related proteins were expressed early, in pre-tangle neurons, but were absent in tangle neurons.

This report suggests that "unfolded protein response activation occurs at an early stage of neurofibrillary degeneration and … that the prolonged activation of the [unfolded protein response] is involved in both tau phosphorylation and neurodegeration in [Alzheimer's Disease] pathogenesis. … Future studies will address the therapeutic opportunities of this pathway for the treatment of [Alzheimer's Disease] and other tauopathies."