PKCε increases endothelin converting enzyme activity and reduces amyloid plaque pathology in transgenic mice

Abstract

Deposition of plaques containing amyloid ␤ (A␤) peptides is a neuropathological hallmark of Alzheimer's disease (AD).Here we demonstrate that neuronal overexpression of the isozyme of PKC decreases A␤ levels, plaque burden, and plaque-associated neuritic dystrophy and reactive astrocytosis in transgenic mice expressing familial AD-mutant forms of the human amyloid precursor protein (APP). Compared with APP singly transgenic mice, APP͞PKC doubly transgenic mice had decreased A␤ levels but showed no evidence for altered cleavage of APP. Instead, PKC overexpression selectively increased the activity of endothelin-converting enzyme, which degrades A␤. The activities of other A␤-degrading enzymes, insulin degrading enzyme and neprilysin, were unchanged. These results indicate that increased neuronal PKC activity can promote A␤ clearance and reduce AD neuropathology through increased endothelin-converting enzyme activity.Alzheimer's disease ͉ phosphorylation ͉ proteolysis ͉ neurodegeneration A lzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized pathologically by the deposition of senile plaques containing amyloid ␤ (A␤) peptides in the brain (1). A␤ is composed primarily of 40-and 42-aa peptides produced from the ␤-amyloid precursor protein (APP) through the combined proteolytic actions of ␤-and ␥-secretase. In cultured cells, treatment with tumor-promoting phorbol esters that activate several PKC isozymes reduces A␤ levels through a mechanism that may involve ␣-secretasemediated cleavage of APP (2, 3). However, although intraparenchymal administration of phorbol esters reduces A␤ levels and deceases amyloid plaque density in mice expressing an amyloidogenic variant of human APP, it does not increase ␣-secretase activity in the brain (4). This finding raises the possibility that PKC decreases A␤ levels in vivo by other mechanisms. Such mechanisms might involve reductions in the activity of amyloidogenic proteases such as BACE1 and ␥-secretase (5).A␤ accumulation is influenced not only by enzymes responsible for its production but also by mechanisms involved in its clearance (5). Several proteases that degrade A␤ in mice include insulin-degrading enzyme (IDE), neprilysin (NEP), and endothelin-coverting enzyme (ECE) 1 and 2 (6). Recently, Leissring et al. (7) demonstrated that transgenic overexpression of IDE or NEP in neurons significantly reduces A␤ levels and plaqueassociated AD pathology. The in vivo function of ECE has been examined in ECE-1-and ECE-2-deficient mice and, in both cases, levels of A␤ were increased compared with WT mice, indicating that these ECEs are A␤-degrading enzymes in vivo (8). However, it is not yet known whether stimulation of ECE activity can reduce A␤ levels or plaque-associated AD pathology, although in one association study, a genetic variant of human ECE1 (ECE1B C-338A) that shows increased promoter activity was associated with a reduced risk of sporadic AD in a French Caucasian population (9). Several in vitro cell culture studies that hav...

PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice

“…However, these activators did substantially increase ECE activity to 180% of control levels . These data suggest that PKC activators reduce A␤ levels by largely increasing the rate of A␤ degradation by ECE and not by activating nonamyloidogenic amyloid precursor protein metabolism, consistent with earlier results showing overexpression of PKC in AD transgenic mice (Choi et al, 2006). However, a recent report did show that PKC activators could also inhibit the amyloidogenic pathway via inhibition of ␤-site of APP cleaving enzyme (Fu et al, 2009).…”

“…Furthermore, PKC reduction has been previously observed in the brains and peripheral tissues of AD versus aged-matched, nondemented control patients (Masliah et al, 1990;Matsushima et al, 1996;Favit et al, 1998). Conversely, PKC has previously been suggested to reduce A␤ by activating ␣-secretase (Skovronsky et al, 2000;Bell et al, 2008), increasing the degradation of A␤ via the endothelinconverting enzyme (ECE) (Choi et al, 2006;) and, most recently, by inhibiting the A␤-forming ␤-secretase (Wang et al, 2008).…”

Reduction of β-Amyloid Levels by Novel Protein Kinase Cϵ Activators

“…Another possible mechanism is by increasing the rate of degradation. A recent report (28) presented evidence that PKC⑀ increases the activity of ECE, an enzyme that degrades A␤. These authors reported that in APP/PKC⑀ transgenic mice, which overexpress PKC⑀, levels of A␤ were lower than in control animals, but there was no change in other A␤-degrading enzymes, such as insulindegrading enzyme or neprilysin, and no change in APP metabolism.…”

Happy birthday protein kinase C: Past, present and future of a superfamily

“…Such selective activators may provide benefits for patients with Alzheimer's disease (AD), in which PKC appears to act both upstream and downstream of beta amyloid (A␤) accumulation in brain tissues. For example, PKC activation with bryostatin 1 decreased A␤ brain deposition in mouse models of AD favoring non-amyloidogenic metabolism of the A␤ precursor [80] and PKC activation decreased brain A␤ accumulation, favoring its clearance [81]. A general outline of PKC therapeutic potential in AD can be found in a recent publication [82].…”