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Endothelin-converting enzymes and related metalloproteases in Alzheimer's disease.

ABSTRACT: The efficient clearance of amyloid-? (A?) is essential to modulate levels of the peptide in the brain and to prevent it from accumulating in senile plaques, a hallmark of Alzheimer's disease (AD) pathology.We and others have shown that failure in A? catabolism can produce elevations in A? concentration similar to those observed in familial forms of AD. Based on the available evidence, it remains plausible that in late-onset AD, disturbances in the activity of A? degrading enzymes could induce A? accumulation, and that this increase could result in AD pathology. The following review presents a historical perspective of the parallel discovery of three vasopeptidases (neprilysin and endothelin-converting enzymes-1 and -2) as important A? degrading enzymes. The recognition of the role of these vasopeptidases in A? degradation, beyond bringing to light a possible explanation of how cardiovascular risk factors may influence AD risk, highlights a possible risk of the use of inhibitors of these enzymes for other clinical indications such as hypertension. We will discuss in detail the experiments conducted to assess the impact of vasopeptidase deficiency (through pharmacological inhibition or genetic mutation) on A? accumulation, as well as the cooperative effect of multiple A? degrading enzymes to regulate the concentration of the peptide at multiple sites, both intracellular and extracellular, throughout the brain.

SUBMITTER: Pacheco-Quinto J

PROVIDER: S-EPMC3677825 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Endothelin-converting enzymes and related metalloproteases in Alzheimer's disease.

Pacheco-Quinto Javier J Herdt Aimee A Eckman Christopher B CB Eckman Elizabeth A EA

Journal of Alzheimer's disease : JAD 20130101

The efficient clearance of amyloid-β (Aβ) is essential to modulate levels of the peptide in the brain and to prevent it from accumulating in senile plaques, a hallmark of Alzheimer's disease (AD) pathology.We and others have shown that failure in Aβ catabolism can produce elevations in Aβ concentration similar to those observed in familial forms of AD. Based on the available evidence, it remains plausible that in late-onset AD, disturbances in the activity of Aβ degrading enzymes could induce Aβ ...[more]

PMID: 22903130

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Project description:This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ42), a peptide strongly associated with AD. Previous studies in mice, demonstrated that targeted overexpression of ACE in CD115+ myelomonocytic cells (ACE10 models) improved their immune responses to effectively reduce viral and bacterial infection, tumor growth, and atherosclerotic plaque. We further demonstrated that introducing ACE10 myelomonocytes (microglia and peripheral monocytes) into the double transgenic APPSWE/PS1ΔE9 murine model of AD (AD+ mice), diminished neuropathology and enhanced the cognitive functions. These beneficial effects were dependent on ACE catalytic activity and vanished when ACE was pharmacologically blocked. Moreover, we revealed that the therapeutic effects in AD+ mice can be achieved by enhancing ACE expression in bone marrow (BM)-derived CD115+ monocytes alone, without targeting central nervous system (CNS) resident microglia. Following blood enrichment with CD115+ ACE10-monocytes versus wild-type (WT) monocytes, AD+ mice had reduced cerebral vascular and parenchymal Aβ burden, limited microgliosis and astrogliosis, as well as improved synaptic and cognitive preservation. CD115+ ACE10-versus WT-monocyte-derived macrophages (Mo/MΦ) were recruited in higher numbers to the brains of AD+ mice, homing to Aβ plaque lesions and exhibiting a highly Aβ-phagocytic and anti-inflammatory phenotype (reduced TNFα/iNOS and increased MMP-9/IGF-1). Moreover, BM-derived ACE10-Mo/MΦ cultures had enhanced capability to phagocytose Aβ42 fibrils, prion-rod-like, and soluble oligomeric forms that was associated with elongated cell morphology and expression of surface scavenger receptors (i.e., CD36, Scara-1). This review explores the emerging evidence behind the role of ACE in AD, the neuroprotective properties of monocytes overexpressing ACE and the therapeutic potential for exploiting this natural mechanism for ameliorating AD pathogenesis.

Dataset Information

Endothelin-converting enzymes and related metalloproteases in Alzheimer's disease.

Publications

Endothelin-converting enzymes and related metalloproteases in Alzheimer's disease.

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