Controlling Calcium Homeostasis Could Stabilize Alzheimer¡¯s Disease

The deficiencies are associated at the cellular level with increased production of the proteotoxic peptide A©¬1-42, and at the organismal level with increased risk of early-onset AD. Modulation of SERCA activity on its own can affect the rate of A©¬ synthesis. Taken together, the data argue that PS1 and PS2 regulate intracellular Ca2+, and that calcium in turn influences production of A©¬ (and thereby the risk and progression of AD).

Another study, by researchers at the Feinstein Institute for Medical Research (Manhasset, NY, USA) identified CALHM1, a calcium pump on the plasma membrane (as opposed to the ER/SR membrane) that is also involved in A©¬ production. A naturally occurring polymorphism in the CALHM1 gene is strongly associated with AD; the authors propose that the mutation interferes with Ca2+ permeability and that this alters A©¬ expression via an as-yet-undetermined mechanism.

When combining the two studies, calcium is seen to be moving in opposite directions; SERCA pumps Ca2+ out of the cytosol into the ER/SR, so a deficiency in SERCA would increase cytosolic Ca2+. In contrast, CALHM1 pumps Ca2+ into the cytosol, so that a deficiency in that protein would decrease cytosolic Ca2+. However, deficiencies in either gene promote AD. The studies suggest that the similar effects on A©¬ levels are mediated by two very different mechanisms.

Amyloid ¥â is a peptide that is the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. Amyloid ¥â also forms aggregates coating cerebral blood vessels in cerebral amyloid angiopathy. These plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers, a protein fold shared by other peptides such as prions associated with protein misfolding diseases. Research on laboratory rats suggests that the two-molecule, soluble form of the peptide is a causative agent in the development of AD.


Related Links:
Feinstein Institute for Medical Research
University of California Irvine