The patterns of BACE2 and ADAM17 only partially overlapped with that of beta-APP. beta-APP, BACE, and ADAM10 mRNAs have also been detected by northern blot in human brain cortex of normal subjects and in Alzheimer's disease subjects.
ADAM10, a disintegrin and metalloprotease that plays a key role in the pathogenesis of Alzheimer's disease, was recently shown to use PrP(c) as a substrate.
The results provide the first in vivo evidence for a proteinase of the ADAM family as an alpha-secretase of APP, reveal activation of ADAM10 as a promising therapeutic target, and support the hypothesis that a decrease in alpha-secretase activity contributes to the development of AD.
This finding suggests that pharmacologic targeting of RA receptors may increase the expression of the alpha-secretase ADAM10 with beneficial effects on AD pathology.
In conclusion, this is a new mechanism by which levels of ADAM10 are regulated and may have implications in a range of human diseases including Alzheimer's disease.
We recently demonstrated that overexpression of ADAM10 in mice transgenic for human AbetaPP (ADAM10 x APP[V717I]) alleviated functional deficits related to Alzheimer's disease.
In summary, we provide the first evidence of ADAM10 as a candidate AD susceptibility gene, and report two potentially pathogenic mutations with incomplete penetrance for late-onset familial AD.
A reciprocal relationship exists between non-amyloidogenic and amyloidogenic APP processing such that impaired ADAM10-mediated proteolysis of the protein serves to enhance amyloidogenic processing (by beta- and gamma-secretases) thereby elevating levels of the amyloid beta (A beta)-peptides responsible for the neuronal death observed in the AD-afflicted brain.
Analyses of ADAM10 promoter activity were performed in human and murine neuroblastoma cell lines and important findings were validated in an AD mouse model.
Proteolytic processing of the amyloid precursor protein by alpha-secretase prevents formation of the amyloid beta-peptide (Abeta), which is the main constituent of amyloid plaques in brains of Alzheimer disease (AD) patients. alpha-Secretase activity is decreased in AD, and overexpression of the alpha-secretase ADAM10 (a disintegrin and metalloprotease 10) in an AD animal model prevents amyloid pathology.
ADAM10 (A disintegrin and metalloproteinase 10) has been demonstrated as an enzyme with protective properties in Alzheimer's disease: in mouse models it not only lowered generation of toxic A-beta peptides and formation of senile plaques but also alleviated learning deficits and enhanced synaptic density.
Additional mechanisms have been suggested for the ability of flavonoids to delay the initiation of and/or slow the progression of AD-like pathology and related neurodegenerative disorders, including a potential to inhibit neuronal apoptosis triggered by neurotoxic species (e.g., oxidative stress and neuroinflammation) or disrupt amyloid β aggregation and effects on amyloid precursor protein processing through the inhibition of β-secretase (BACE-1) and/or activation of α-secretase (ADAM10).
The findings raise the possibility that the adenovirus vaccine Ad-10×Aβ3-10-CpG could be a safe and effective alternative for immunotherapy in Alzheimer's disease.
Results from this investigation suggest that the ADAM10 rs514049-rs653765 C-A promoter haplotype is associated with: (1) higher CSF sAPPα levels in cognitively normal controls compared with Alzheimer's disease (AD) patients, (2) higher postmortem brain hippocampus, but not cerebellum, ADAM10 protein levels in subjects with low plaque scores compared with those with high plaque scores, and (3) higher promoter activity for promoter-only reporter constructs compared with promoter 3' untranslated region (3'UTR) constructs in the human neuroblastoma SHSY5Y cell line, but not in HepG2 or U118 cell lines.
MiRNA binding sites in the human ADAM10 3' untranslated region were predicted using the RNA22, RNAhybrid and miRanda programs and ranked by specific selection criteria with respect to AD such as differential regulation in AD patients and tissue-specific expression.