The amyloid- peptide (A) can generate cytotoxic oligomers, and their accumulation is thought to underlie the neuropathologic changes found in Alzheimer's disease. Known inhibitors of A polymerization bind to undefined structures and can work as nonspecific aggregators, and inhibitors that target conformations that also occur in larger A assemblies may even increase oligomerderived toxicity. Here we report on an alternative approach whereby ligands are designed to bind and stabilize the 13-26 region of A in an ␣-helical conformation, inspired by the postulated A native structure. This is achieved with 2 different classes of compounds that also reduce A toxicity to cells in culture and to hippocampal slice preparations, and that do not show any nonspecific aggregatory properties. In addition, when these inhibitors are administered to Drosophila melanogaster expressing human A 1-42 in the central nervous system, a prolonged lifespan, increased locomotor activity, and reduced neurodegeneration is observed. We conclude that stabilization of the central A ␣-helix counteracts polymerization into toxic assemblies and provides a strategy for development of specific inhibitors of A polymerization.amyloid fibrils ͉ neurodegenerative disease ͉ protein misfolding ͉ Alzheimer's disease A lzheimer's disease is a progressive neurodegenerative disorder that is characterized by cerebral extracellular amyloid plaques and intracellular neurofibrillary tangles (1). Classically, the amyloid cascade hypothesis (2) states that Alzheimer's disease is caused by fibril and plaque formation of amyloid- peptide (A) in the central nervous system. More recently, the hypothesis has been modified to include A assemblies of sizes intermediate to monomeric and fibrillar forms, which today are considered to be the main source of cytotoxicity (3). Such A assemblies include low-number oligomers and larger assemblies known as protofibrils, globulomers, Alzheimer's disease diffusible ligands, or A*56 (4-7). A is cleaved from an integral membrane protein, the amyloid  precursor protein (APP), predominantly as a 40-residue peptide (A 1-40 ). In addition, a C-terminally elongated 42-residue version can be excised (A 1-42 ); it is this longer variant that is the main constituent of parenchymal amyloid deposits (8).The link between A aggregation and Alzheimer's disease implies that inhibitors of this process should be able to slow down disease progression. A number of low-molecular-mass A aggregation inhibitors have been identified by use of screens of compound libraries as well as rational design strategies. The resulting inhibitors include such chemically diverse compounds as curcumin, inositol, and nicotine (9, 10). The screens have identified inhibitors of fibril formation that similarly to the rationally designed inhibitors are predicted to bind to A in an elongated, -strand-like conformation and prevent its polymerization. A potential problem with this strategy is that blocking the later stages of fibril formation will favor t...
Alzheimer disease is characterized by extracellular plaques composed of A peptides. We show here that these plaques also contain the serine protease inhibitor neuroserpin and that neuroserpin forms a 1:1 binary complex with the N-terminal or middle parts of the A 1-42 peptide. This complex inactivates neuroserpin as an inhibitor of tissue plasminogen activator and blocks the loop-sheet polymerization process that is characteristic of members of the serpin superfamily. In contrast neuroserpin accelerates the aggregation of A 1-42 with the resulting species having an appearance that is distinct from the mature amyloid fibril. Neuroserpin reduces the cytotoxicity of A 1-42 when assessed using standard cell assays, and the interaction has been confirmed in vivo in novel Drosophila models of disease. Taken together, these data show that neuroserpin interacts with A 1-42 to form off-pathway non-toxic oligomers and so protects neurons in Alzheimer disease.Alzheimer disease is the most common form of dementia. The pathological features are characterized by neurofibrillary tangles and extracellular A plaques. The plaques are composed of 42 (A 1-42 )-and to a lesser extent 40 (A 1-40 )-amino acid fragments of the amyloid precursor protein (1). Overproduction of the more aggregatory A 1-42 peptide is believed to cause neuronal dysfunction and death in most sporadic and familial forms of Alzheimer disease. Although insoluble plaques of A 1-42 are a classic feature of the brains of patients with Alzheimer disease, these plaques are also present in some healthy, elderly individuals (2). This discrepancy, and the observation that soluble A is a better marker of cognitive decline (3), has led to the proposal that mature amyloid plaques are an end stage aggregation product and that the directly neurotoxic species occur earlier in the aggregation pathway (4, 5). The description of soluble oligomers of A that can cause neuronal dysfunction and death (4 -6) has emphasized the importance of understanding the pathways and kinetics of A aggregation. The presence of ancillary proteins that interact with A may stabilize particular aggregation intermediates or seed-specific patterns of aggregation that have distinct toxic properties. Of particular interest in this regard are several proteins that are associated with  amyloid plaques such as apolipoprotein E (7) and the serine protease inhibitor (serpin) ␣ 1 -antichymotrypsin (8). The role of these proteins is underscored by the finding that the E4 polymorphism of apolipoprotein E is the most powerful genetic risk factor for the development of sporadic Alzheimer disease (9, 10), most likely because it accelerates the deposition of A in the brain (11-13). ␣ 1 -Antichymotrypsin is also found in the majority of senile plaques (8), with cerebrospinal fluid concentrations being consistently raised in patients with Alzheimer disease (14). Depending on the relative molar ratio, ␣ 1 -antichymotrypsin may accelerate or inhibit the aggregation of the A peptide in vitro (15,16).We h...
International audienceThe newly synthesized surfactant protein C precursor (proSP-C) is an integral endoplasmic reticulum (ER) membrane protein with a single metastable polyVal α-helical transmembrane domain that comprises two thirds of the mature peptide. More than 20 mutations in the ER-lumenal, C-terminal domain of proSP-C (CTC), are associated with interstitial lung disease (ILD), and some of the mutations cause intracellular accumulation of cytotoxic protein aggregates and a corresponding decrease in mature SP-C. Here it is shown that (i) human embryonic kidney cells expressing the ILD associated mutants proSP-CL188Q and proSP-CΔExon4 accumulate Congo red positive amyloid-like inclusions, while cells transfected with the mutant proSP-CI73T do not, (ii) transfection of CTC into cells expressing proSP-CL188Q results in a stable CTC/proSP-CL188Q complex, increased proSP-CL188Q half life and reduced formation of Congo red positive deposits, (iii) replacement of the metastable polyVal transmembrane segment with a stable polyLeu likewise prevents formation of amyloid-like proSP-CL188Q aggregates, and (iv) binding of recombinant CTC to non-helical SP-C blocks SP-C amyloid fibril formation. These data suggest that CTC can prevent the polyVal segment of proSP-C from promoting formation of amyloid-like deposits during biosynthesis, by binding to non-helical conformations. Mutations in the Brichos domain of proSP-C may lead to ILD via loss of CTC chaperone function
Amyloid fibrils are found in approximately 25 different diseases, including Alzheimer's disease. Lung surfactant protein C (SP-C) forms fibrils in association with pulmonary disease. It was recently found that the C-terminal domain of proSP-C (CTC), which is localized to the endoplasmic reticulum (ER) lumen, protects the transmembrane (TM) part of (pro)SP-C from aggregation into amyloid until it has a folded into an alpha-helix. CTC appears to have a more general anti-amyloid effect by also acting on TM regions of other proteins. Here we investigate interactions of CTC with the amyloid beta-peptide (Abeta) associated with Alzheimer's disease and medin, a peptide that forms fibrils in the most common form of human amyloid. CTC prevents fibril formation in Abeta and medin and forms a complex with Abeta oligomers, as judged by size-exclusion chromatography and electrospray ionization mass spectrometry. These data suggest that CTC functions as a chaperone that acts preferentially against unfolded TM segments and structural motifs found during amyloid fibril formation, a mechanism that may be exploited in forming a basis for future anti-amyloid therapy.
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