Abstract
Abnormal elevation of amyloid β-peptide (Aβ) levels in the brain is the primary trigger for neuronal cell death specific to Alzheimer’s disease (AD). It is now evident that Aβ levels in the brain are manipulable due to a dynamic equilibrium between its production from the amyloid precursor protein (APP) and removal by amyloid clearance proteins. Clearance can be either enzymic or non-enzymic (binding/transport proteins). Intriguingly several of the main amyloid-degrading enzymes (ADEs) are members of the M13 peptidase family (neprilysin (NEP), NEP2 and the endothelin converting enzymes (ECE-1 and -2)). A distinct metallopeptidase, insulin-degrading enzyme (IDE), also contributes to Aβ degradation in the brain. The ADE family currently embraces more than 20 members, both membrane-bound and soluble, and of differing cellular locations. NEP plays an important role in brain function terminating neuropeptide signals. Its decrease in specific brain areas with age or after hypoxia, ischaemia or stroke contribute significantly to the development of AD pathology. The recently discovered mechanism of epigenetic regulation of NEP (and other genes) by the APP intracellular domain (AICD) and its dependence on the cell type and APP isoform expression suggest possibilities for selective manipulation of NEP gene expression in neuronal cells. We have also observed that another amyloid-clearing protein, namely transthyretin (TTR), is also regulated in the neuronal cell by a mechanism similar to NEP. Dependence of amyloid clearance proteins on histone deacetylases and the ability of HDAC inhibitors to up-regulate their expression in the brain opens new avenues for developing preventive strategies in AD.
Highlights
Overproduction and accumulation in the brain of abnormally high concentrations of the amyloid-β (Aβ) peptide and its oligomers causing synaptic loss and neuronal cell death are considered among the principal pathological events underlying neurodegeneration and Alzheimer’s disease (AD; Hardy and Higgins, 1992; Walsh et al, 2002; Hardy, 2009)
Our studies have demonstrated that experimental four-vessel occlusion ischaemia in rats resulted in down-regulation of NEP and endothelin-converting enzyme (ECE)-1 as well as up-regulation of amyloid precursor protein (APP) and BACE both in the cortex and hippocampus (Nalivaeva et al, 2004, 2005)
Along with the age-related decrease of NEP expression observed in neuronal cells, Apelt and colleagues have reported up-regulation of this enzyme in reactive astrocytes surrounding amyloid plaques in AD transgenic mice (Apelt et al, 2003) which is considered to be a compensatory reaction of a specific set of brain cells possessing a protective function
Summary
Overproduction and accumulation in the brain of abnormally high concentrations of the amyloid-β (Aβ) peptide and its oligomers causing synaptic loss and neuronal cell death are considered among the principal pathological events underlying neurodegeneration and Alzheimer’s disease (AD; Hardy and Higgins, 1992; Walsh et al, 2002; Hardy, 2009). Reduced NEP mRNA levels were reported in the hippocampus and temporal gyrus of AD patients suggesting a relationship between NEP activity and deficient degradation of Aβ peptide leading to high number of senile plaques in these brain areas (Yasojima et al, 2001).
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