In total, MMP9 inhibition can facilitate Aβ clearance across the BBB, which could be an effective approach to lowering Aβ levels in the brain and mitigating the AD phenotype, particularly in subjects carrying the apoE4 allele.
Using this method to select from synthetic human antibody libraries, we isolated panels of mAbs inhibiting 5 targets of 4 main protease classes: matrix metalloproteinases (MMP-14, a predominant target in metastasis; MMP-9, in neuropathic pain), β-secretase 1 (BACE-1, an aspartic protease in Alzheimer's disease), cathepsin B (a cysteine protease in cancer), and Alp2 (a serine protease in aspergillosis).
Additionally according to the reported changes of MMP-2, MMP-9 and MAPKs (ERK, P38 and JNK) in AD pathology the hippocampal contents of these proteins were determined.
Our data show that in both AD animal models, the cerebrovasculature is activated and overexpresses amyloid beta, thrombin, tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and matrix metalloproteinase 9.
Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimer disease.
However, after adjusting the p-values for multiple comparisons, these results were not statistically significant, suggesting that genetic variations in MMEL1, ECE1, ECE2, AGER, PLG, PLAT, NR1H3, MMP3, LRP1, TTR, NR1H2, and MMP9 genes do not play major role among the Finnish AD patient cohort.
Minocycline also diminished altered matrix metalloproteinase 9, inducible nitric oxide synthase, and microglial activation (CD40); improved cognitive behavior; and normalized pro-NGF levels in a transgenic mouse AD model.
Analysis of MMP-3 -1171 5A/6A allele frequencies showed that the 6A allele (with reduced promoter activity) was associated with AD; the MMP-9C-1562T polymorphism was not.
The cellular distribution of MMP-9 is altered in AD because 76% of the total 100 kDa enzyme activity is found in the soluble fraction of control specimens, whereas only 51% is detectable in the same fraction from AD specimens.