Cleavage of amyloid precursor protein (APP) by the Alzheimer's β-secretase (BACE1) is a key step in generating amyloid β-peptide, the main component of amyloid plaques. Here we report evidence that heparan sulfate (HS) interacts with β-site APP-cleaving enzyme (BACE) 1 and regulates its cleavage of APP. We show that HS and heparin interact directly with BACE1 and inhibit in vitro processing of peptide and APP substrates. Inhibitory activity is dependent on saccharide size and specific structural characteristics, and the mechanism of action involves blocking access of substrate to the active site. In cellular assays, HS specifically inhibits BACE1 cleavage of APP but not alternative cleavage by α-secretase. Endogenous HS immunoprecipitates with BACE1 and colocalizes with BACE1 in the Golgi complex and at the cell surface, two of its putative sites of action. Furthermore, inhibition of cellular HS synthesis results in enhanced BACE1 activity. Our findings identify HS as a natural regulator of BACE1 and suggest a novel mechanism for control of APP processing.
Hyaluronan (HA) is a high-molecular weight glycosaminoglycan that is involved in an extracellular matrix (ECM) organization and cell adhesion, essential to a wide range of normal
p(25-35) is a fragment of P-amyloid, that retains its properties. N-methylated derivatives of P(25-35) can block hydrogen bonding on the outer edge of the assembling amyloid, so preventing the aggregation and inhibiting the toxicity of the wild type peptide.The effects are assayed by Congo red and Thioflavin T binding, electron microscopy and an MTT toxicity assay. N-methyl Gly 25 has similar properties to wild-type, while five have varying effects on prefolded fibrils and fibril assembly. In particular, N-methyl Gly33 is able to completely prevent fibril assembly and reduces the toxicity of prefolded amyloid. With N-methyl Leu34 the fibril morphology is altered and toxicity reduced. P(25-35) structure in aqeuous solution was studied by small angle neutron reflection (SANS). The protofibrillar aggregates are best described by a cylindrical or toroidal model with radius of 140 Angstroms and height of 53 Angstroms. No aggregates form in the presence of N-methyl Gly33. We suggest that the use of N-methylated derivatives of amyloidogenic peptides and proteins could provide a general solution to the problem of amyloid deposition and toxicity, and that SANS is a unique technique for the direct observation of protofibril formation and destruction in solution.28 Chronic nicotine treatment reduces beta-amyloidosis L Court, E.Alzheimer's disease is characterised by beta-amyloid plaques, and inhibition of beta-amyloid accumulation may be essential for effective therapy in this disorder. Previous in vitro studies have indicated protective effects of nicotine against amyloid beta peptide deposition and toxicity. In the present study the effect of long term nicotine on human age related Alzheimer-like pathology was assessed by comparison of non-demented elderly tobacco smokers and non-smokers. In tobacco users there was reduced beta-amyloid plaque deposition in the hippocampus and entorhinal cortex compared with age-matched non-smokers, but no significant change in neurofibrillary tangles. Chronic nicotine treatment of transgenic mice (APPsw)(from 9 months of age for 5.5 months), which also develop beta-amyloid plaques, caused greatly reduced plaque density in the neocortex and hippocampus, together with reduced levels of insoluble, but not soluble, 1-40 and 1-42 amyloid peptides. Chronic nicotine can therefore reduce beta-amyloid deposition in both elderly humans and a mouse model of Alzheimer-like pathology and nicotinic drugs may be a feasible neuroprotective therapeutic approach in Alzheimer's disease.29 Proteolytic processing of the amyloid precursor protein by a-secretase Alzheimer's Disease is the most common form of dementia in the elderly and is characterised by the deposition of plaques of a 4kDa peptide called AP. AP is cleaved from a larger protein called the amyloid precursor protein by the action of two proteases termed the P and y secretases. Another protease, the a-secretase prevents the formation of AP by cleaving APP in the centre of the AP region. The a-secretase has been independently identified as being on...
Please refer to abstract number 89. This abstract was originally submitted as a poster, and on the basis of its scientific interest and merit, was chosen by the colloquium organizers to be presented as an oral communication, as well as a poster.
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