Another weapon against amyloid

Abstract

A lzheimer'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 ␤-amyloid (A␤), 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 A␤ vaccines, metal chelators, and derivatives of Congo red dye, which bind A␤. In this issue of PNAS, Robert Messing and colleagues (1) report a finding that suggests a new strategy for stimulating the enzymatic breakdown of A␤, which could produce benefit in AD.This strategy is based on the enzyme PKC, a serine͞threonine kinase that catalyzes the calcium-and phospholipiddependent 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 PKC␦ in reperfusion injury after experimental stroke, consistent with work from Mochly-Rosen and colleagues (3) showing that a PKC␦ inhibitor reduced infarct size. The present study (1) builds on previous findings that phorbol esters reduce A␤ levels and the number of amyloid plaques in AD-transgenic mice (4) and that PKC decreases A␤ levels in cell culture (5). These and other threads that link PKC and A␤ are discussed in a recent review (6).Messing and colleagues (1) crossed two lines of transgenic mice, one that overexpresses PKC in neurons and another that expresses a mutant form of APP (the Indiana or V717F mutation) found in some patients with the rare familial form of AD. The latter mice exhibit some features of clinical AD, including the age-dependent deposition of extracellular amyloid plaques in selected brain regions. Plaque density, astrogliosis, and alterations in neurites were reduced in PKC -transgenic͞ APP V717F compared with APP V717F mutant mice. Similar findings were obtained with other PKC and APP transgenics. Contrary to expectations, however, A␤ synthesis was unaffected by PKC overexpression. Instead, PKC seemed to act by stimulating the degradation of A␤.A␤ is a substrate for several enzymes, including insulin-degrading enzyme and neprilysin, the activities of which were unaltered in PKC transgenics. However, the activity of another A␤-degrading enzyme, endothelin-converting enzyme (ECE) (7), was increased in hippocampus and cerebral neocortex of these mice. Previous cell-culture studies suggested that the effect of phorbol esters on ECE expression was mediated through the transcription factor Ets-1. Messing and colleagues (1) concluded that amyloid deposition was d...