Surprising as it may seem, presenilins—the enzymes at the heart of the proteolytic γ-secretase complex that unleashes Aβ peptides—are essential to prevent age-related cognitive deficits and neurodegeneration. That's the conclusion from research carried out in Jie Shen's lab at Brigham and Women's Hospital, Boston. Shen presented the data at the Society for Neuroscience meeting in New Orleans last year (see ARF related news story), and published yesterday in the online version of Neuron, due out in print next week.
Because presenilins are essential for embryonic development, first author Carlos Saura and colleagues used a technique called a conditional knockout to eliminate expression of the two presenilin genes in the forebrain of postnatal mice. The mice then developed age-dependent neurodegeneration, scoring progressively worse in tests designed to measure their memory and learning ability. Saura and colleagues correlated these declines with dysregulation of several signal transduction pathways, including those involving NMDA receptors/CaMKII, CREB/CBP, and with increased activity of Cdk5/p25 and hyperphosphorylated tau. (Tau is the major protein in the intracellular neurofibrillary tangles that clog the neurons of Alzheimer's patients, and Cdk5 phosphorylates tau.)
Presenilin mutations are one cause of familial Alzheimer's disease. These mutations have long been said to be gain-of-function, i.e., they increase cleavage of the Aβ precursor protein and release more Aβ, which may then end up in amyloid plaques if it is not cleared quickly enough. Shen’s new data does not dispute this, but suggests that PS mutations may also cause a loss of function that contributes to the pathology of AD and complicates the picture. The data also suggests that discretion should be the better part of valor when it comes to γ-secretase inhibitors as potential AD therapeutics.—Tom Fagan