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Alzheimer's Disease

The nervous system is just as sensitive to the assaults of systemic inflammation as other body systems. Inflammation plays a critical role in the development of debilitating neurological conditions such as Alzheimer’s disease, which some doctors describe as “the brain on fire”. In fact, it is now more appropriate to call Alzheimer’s and inflammatory disease. The phrase “degenerative brain disease” does not appropriate describe the fact a root cause is the active inflammation taking place in the brain.
We now know that systemic inflammation increases production of the pro-inflammatory cytokine TNF-alpha (tumor necrosis factor alpha).
A recent study of three hundred patients noted that increased serum levels of TNF-alpha due to systemic inflammation are associated with increased rate of cognitive decline.
Research has shown, without a doubt, that Wobenzym decreases serum levels of TNF-alpha. As we saw in the rheumatoid arthritis studies, patients treated with Wobenzym have TNF-alpha levels less than half the levels seen in untreated patients. This decrease is the pro-inflammatory cytokine TNF-alpha is one of the mechanisms by which Wobenzym can decrease the progression of Alzheimer’s disease.
I cannot overemphasize how important it is to have TNF-alpha levels lowered. If the levels of that pro-inflammatory cytokine are not kept in check, we see increased production of amyloid beta peptides, the main component of the plaques that appear in the brains of Alzheimer’s patients. By decreasing TNF-alpha, Wobenzym can decrease the formation of those dangerous amyloid beta peptides.
Another important finding is that Wobenzym can promote the breakdown and clearance of these amyloid beta peptides. A number of studies show that when alpha-2-macroglobulin is activated – which we discussed earlier as a primary action of Wobenzym, the amyloid beta peptides are broken down, and removed from tissues at an accelerated rate.
                    From FREQUENTLY ASKED QUESTIONS, with answers by Joseph J Collins, RN, ND
                    Read the special section: : Controlling Systemic Inflammation with Systemic Enzyme Support

What the literature says about Systemic Enzyme Support and:

Alzheimer’s Disease

Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism.

Lauer D, Reichenbach A, Birkenmeier G. Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism.  Exp Neurol. 2001 Feb;167(2):385-92.

Peptides derived from proteolytic degradation of the amyloid precursor protein, e.g., amyloid beta (A beta), are considered to be central to the pathology of Alzheimer's disease (AD). Soluble A beta is present in measurable concentrations in cerebrospinal fluid and blood. There are indications that soluble A beta present in circulation can cross the blood-brain barrier via transcytosis mediated by brain capillary endothelial cells. It implies that A beta originating from circulation may contribute to vascular and parenchymal A beta deposition in  AD. Enhancing of A beta catabolism mediated by proteolytic degradation or receptor-mediated endocytosis could be a key mechanism to maintain low concentrations of soluble A beta. To launch A beta clearance we have exploited the A beta-degrading activity of diverse alpha 2-macroglobulin (alpha 2-M)-proteinase complexes. Complexes with trypsin, alpha-chymotrypsin, and bromelain strongly degrade (125)I-A beta 1--42 whereas complexes with endogenous  proteinases, e.g., plasmin and prostate-specific antigen, were not effective. A beta degradation by the complexes was not inhibited by alpha 1-antichymotrypsin and soybean trypsin inhibitor which normally would inactivate the free serine proteinases. A prerequisite for A beta degradation is its binding to specific binding sites in alpha 2-M that may direct A beta to the active site of the caged proteinase. Ex vivo, enhanced degradation of (125)I-A beta 1--42 in blood could be achieved upon oral administration of high doses of proteinases to volunteers.  These results suggest that up-regulation of A beta catabolism could probably reduce the risk of developing AD by preventing A beta accumulation in brain and vasculature.
External Link: PMID:11161627
Poster Reference Number 7.

Degradation of amyloid beta-protein by a serine protease-alpha2-macroglobulin complex.

Qiu WQ, Borth W, Ye Z, Haass C, Teplow DB, Selkoe DJ. Degradation of amyloid beta-protein by a serine protease-alpha2-macroglobulin complex. 1: J Biol Chem. 1996 Apr 5;271(14):8443-51. Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Progressive cerebral deposition of the amyloid beta-peptide (Abeta) is an early and constant feature of Alzheimer's disease. Abeta is derived by proteolysis from the beta-amyloid precursor protein. beta-Amyloid precursor protein processing and the generation of Abeta have been extensively characterized, but little is known  about the mechanisms of degradation of this potentially neurotoxic peptide.  
We identified and purified a proteolytic activity in culture medium that can degrade secreted Abeta but not larger proteins in the medium. Detection of the activity in conditioned medium required the presence of fetal bovine serum and the passage of the cells with a pancreatic trypsin preparation. Its inhibitor profile showed  that the activity was a serine protease other than trypsin or chymotrypsin. The protease occurs as a stable approximately 700-kDa complex with the inhibitor, alpha2-macroglobulin (alpha2M), that retains activity against small substrates such as Abeta.
Its NH2-terminal sequence suggests that the protease is previously unidentified. Our results indicate that the Abeta-degrading protease we have detected is a non-trypsin component of a pancreatic trypsin preparation or else derives from a zymogen in serum that is activated by a protease in the latter preparation. Because Abeta-bearing plaques in Alzheimer's disease brain contain both alpha2M and receptors of alpha2M-protease complexes, the same or a similar alpha2M-protease complex could arise in vivo and play a role in Abeta clearance.
External Link: PMID: 8626544
Poster Reference Number 8.

alpha2-Macroglobulin as a beta-amyloid peptide-binding plasma protein.

Du Y, Ni B, Glinn M, Dodel RC, Bales KR, Zhang Z, Hyslop PA, Paul SM. alpha2-Macroglobulin as a beta-amyloid peptide-binding plasma protein. J Neurochem. 1997 Jul;69(1):299-305. Division of CNS Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, U.S.A.

The beta-amyloid peptide (A beta) is a normal proteolytic processing product of the amyloid precursor protein, which is constitutively expressed by many, if not  most, cells. For reasons that are still unclear, A beta is deposited in an aggregated fibrillar form in both diffuse and senile plaques in the brains of patients with Alzheimer's disease (AD). The factor(s) responsible for the clearance of soluble A beta from biological fluids or tissues are poorly understood. We now report that human alpha2-macroglobulin (alpha2M), a major circulating endoproteinase inhibitor, which has recently been shown to be present in senile plaques in AD, binds 125I-A beta(1-42) with high affinity (apparent dissociation constant of 3.8 x 10(-10) M). Approximately 1 mol of A beta is bound per mole of alpha2M. Both native and methylamine-activated alpha2M bind 125I-A beta(1-42). The binding of 125I-A beta(1-42) to alpha2M is enhanced by micromolar concentrations of Zn2+ (but not Ca2+) and is inhibited by noniodinated A beta(1-42) and A beta(1-40) but not by the reverse peptide A beta(40-1) or the cytokines interleukin 1beta or interleukin 2. alpha1-Antichymotrypsin, another plaque-associated protein, inhibits both the binding of 125I-A beta(1-42) to alpha2M as well as the degradation of 125I-A beta(1-42) by proteinase-activated alpha2M. Moreover, the binding of 125I-A beta(1-42) to alpha2M protects the peptide from proteolysis by exogenous trypsin. These data suggest that alpha2M may function as a carrier protein for A beta and could serve to either facilitate or impede clearance of A beta from tissues such as the brain.
External Link: PMID: 9202323
Poster Reference Number 9.

Alpha2-macroglobulin associates with beta-amyloid peptide and prevents fibril formation.

Hughes SR, Khorkova O, Goyal S, Knaeblein J, Heroux J, Riedel NG, Sahasrabudhe S. Alpha2-macroglobulin associates with beta-amyloid peptide and prevents fibril formation. 1: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3275-80. Biotechnology Group and the Central Nervous System Disease Group, Hoechst Marion. Roussel, Inc., P.O. Box 6800, Bridgewater, NJ 08876-0800, USA. 800, USA.

 We have used the yeast two-hybrid system to isolate cDNAs encoding proteins that  specifically interact with the 42-aa beta-amyloid peptide (Abeta), a major constituent of senile plaques in Alzheimer's disease. The carboxy terminus of alpha2-macroglobulin (alpha2M), a proteinase inhibitor released in response to inflammatory stimuli, was identified as a strong and specific interactor of Abeta, utilizing this system. Direct evidence for this interaction was obtained by co-immunoprecipitation of alpha2M with Abeta from the yeast cell, and by formation of SDS-resistant Abeta complexes in polyacrylamide gels by using synthetic Abeta and purified alpha2M. The association of Abeta with alpha2M and various purified amyloid binding proteins was assessed by employing a method measuring protein-protein interactions in liquid phase. The dissociation constant by this technique for the alpha2M-Abeta association using labeled purified proteins was measured (Kd = 350 nM). Electron microscopy showed that a 1:8 ratio  of alpha2M to Abeta prevented fibril formation in solution; the same ratio to Abeta of another acute phase protein, alpha1-antichymotrypsin, was not active in  preventing fibril formation in vitro. These results were corroborated by data obtained from an in vitro aggregation assay employing Thioflavine T. The interaction of alpha2M with Abeta suggests new pathway(s) for the clearance of the soluble amyloid peptide.
External Link: PMID: 9501253
Poster Reference Number 10.

Beta-amyloid peptide binds equivalently to binary and ternary alpha2-macroglobulin-protease complexes.

Mettenburg JM, Gonias SL. Beta-amyloid peptide binds equivalently to binary and ternary alpha2-macroglobulin-protease complexes. Protein J. 2005 Feb;24(2):89-93. Department of Biochemistry and Molecular Genetics University of Virginia School of Medicine, Charlottesville, Virginia, 22908, USA.

 alpha2-Macroglobulin (alpha2M) is a protease inhibitor that has separate binding  sites for transforming growth factor-beta (TGF-beta) and beta-amyloid peptide (Abeta), both of which have been identified in the beta2M sequence. In the 3D-structure of alpha2M, TGF-beta occupies the alpha2M central cavity, overlapping with the space that can accommodate up to two molecules of protease.  As a result, ternary alpha2M-protease complexes (2 mol protease/mol alpha2M) have been reported to not bind TGF-beta. The goal of the present study was to test whether binding of Abeta to alpha2M is controlled by steric constraints imposed by associated proteases, similarly to TGF-beta. We confirmed that binary alpha2M-trypsin complex (1 mol trypsin/mol alpha2M) binds increased amounts of TGF-beta1, compared with native alpha2M, while ternary alpha2M-trypsin complex binds substantially decreased amounts of TGF-beta1. By contrast, Abeta-binding to binary and ternary alpha2M trypsin complex was equivalent. In both cases, binding was substantially increased compared with the negligible level observed with native alpha2M. Plasmin is a large protease (Mr approximately 82,000) that substantially occupies the alpha2M central cavity; however, alpha2M-plasmin complex also bound increased amounts of Abeta, compared with native alpha2M. We conclude that Abeta accesses its binding site, in alpha2M, from outside the alpha2M central cavity. The TGF-beta- and Abeta-binding sites are spatially separated not only in the primary sequence of alpha2M, but also in the 3D-structure.
External Link: PMID: 16003950
Poster Reference number 11.

Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons.

Qiu Z, Strickland DK, Hyman BT, Rebeck GW. Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons. 1: J Neurochem. 1999 Oct;73(4):1393-8. Alzheimer Research Unit, Massachusetts General Hospital and Harvard Medical School, Boston 02129, USA.

Apolipoprotein E and alpha2-macroglobulin (alpha2M) are genetic risk factors for  late-onset Alzheimer's disease, and both bind a cell surface receptor, the low-density lipoprotein receptor-related protein (LRP). To investigate the role of LRP on preventing the accumulation of beta-amyloid peptide (A beta), we examined the effects of alpha2M on the clearance of endogenous A beta. Studies were performed in primary Tg2576 transgenic mouse cortical neuronal cultures expressing human mutant amyloid precursor protein (APP) 695. This system allowed  us to follow endogenous A beta using immunoblots to detect monomeric forms of the peptide. A beta and APP levels were measured in conditioned media. We found that  activated alpha2M (alpha2M*) substantially decreased soluble A beta levels and had no effect on secreted or full-length APP levels. Native alpha2M, which is not a ligand for LRP, did not affect A beta levels. The receptor-associated protein,  which inhibits interaction of all ligands with LRP in vitro, prevented alpha2M*-induced decreases of soluble A beta levels. These data suggest that alpha2M* affects soluble A beta clearance rather than A beta production. Further  studies showed that similar A beta clearance via an LRP-mediated pathway was observed after treatment with another LRP ligand, lactoferrin. Taken together, these data demonstrate that alpha2M* enhances the clearance of soluble A beta via LRP in cortical neurons.
External Link: PMID: 10501182
Poster Reference Number 12.