Another weapon against amyloid

Abstract

Alzheimer’s disease (AD) is one of those conditions that, like cancer in earlier generations, inspires particular terror among the general public. Therapeutic advances have lagged behind insights into genetics and pathophysiology, and although β-amyloid (Aβ), the product of amyloid precursor protein (APP) cleavage, remains the leading suspect among proposed pathogenic factors, its causal role in AD has not been established with certainty. At present, patients with AD have access to two approved specific treatments, acetylcholinesterase inhibitors and the glutamate receptor antagonist memantine, neither of which is dramatically effective. Several experimental approaches are also under study, including Aβ vaccines, metal chelators, and derivatives of Congo red dye, which bind Aβ. In this issue of PNAS, Robert Messing and colleagues (1) report a finding that suggests a new strategy for stimulating the enzymatic breakdown of Aβ, which could produce benefit in AD. This strategy is based on the enzyme PKC, a serine/threonine kinase that catalyzes the calcium- and phospholipid-dependent phosphorylation of protein substrates and is also a receptor for phorbol esters. Messing and colleagues (1) have been studying PKC for many years, especially the neurological effects of PKC isozymes. For example, one recent study (2) implicated neutrophil PKCδ in reperfusion injury after experimental stroke, consistent with work from Mochly-Rosen and colleagues (3) showing that a PKCδ inhibitor reduced infarct size. The present study (1) builds on previous findings that phorbol esters reduce Aβ levels … *E-mail: dgreenberg{at}buckinstitute.org