Treating the Cause of Alzheimer’s Disease

Evidence from scientists worldwide supports the hypothesis that gradual buildup of the amyloid Aβ peptide (Aβ) in memory regions of the brain causes Alzheimer’s disease (AD). Aβ is generated when two enzymes (protein-cutting molecules) cut the Amyloid Parent Protein (APP): an enzyme called β-secretase makes the first cut, and an enzyme called γ-secretase makes the second cut. The released Aβ fragment of APP can then short-circuit nerve cells and build up in "amyloid plaques.”

Over the past decade, Drs. Michael Wolfe and Dennis Selkoe and their coworkers have designed small drug-like compounds to help elucidate the mechanisms of Alzheimer’s disease, and they have also identified γ-secretase itself. Recently, they discovered that γ-secretase is inhibited (and thus Aβ lowered) by certain compounds called “kinase inhibitors.” This discovery, which builds on earlier work by Nobel laureate Paul Greengard, has important therapeutic implication: these “kinase inhibitors” block the cutting of APP by γ-secretase in a special way that does not block the cutting of another protein needed by healthy cells. This ability to selectivity lower Aβ without affecting the healthy role of γ-secretase makes these and similar compounds that they have identified as highly promising starting points to develop an effective and safe medicine for Alzheimer’s disease.

Their extensive experience combining biology and chemistry to decipher AD places their new LEAD laboratory in an unparalleled position to refine and test promising small compounds that have emerged from their research and that of others. As LEAD improves these compounds using medicinal chemistry, they will test them in animal models of AD already available here.

With the backing of private philanthropic contributions, LEAD will engage in this crucial scientific work nimbly and non-bureaucratically. If compounds are identified that show strong therapeutic potential, seeking a partner in the pharmaceutical industry to sponsor the initiation of clinical trials will be pursued. Continued support could make the world of difference in the fight to treat – and ultimately prevent – Alzheimer’s disease.