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Metabolite-initiated protein misfolding may trigger Alzheimer's disease.

ABSTRACT: Anfinsen showed that a protein's fold is specified by its sequence. Although it is clear why mutant proteins form amyloid, it is harder to rationalize why a wild-type protein adopts a native conformation in most individuals, but it misfolds in a minority of others, in what should be a common extracellular environment. This discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease. One possibility is that an abnormal metabolite, generated only in some individuals, covalently modifies the protein or peptide and causes it to misfold, but evidence for this is sparse. Candidate metabolites are suggested by the recently appreciated links between Alzheimer's disease (AD) and atherosclerosis, known chronic inflammatory metabolites, and the newly discovered generation of ozone during inflammation. Here we report detection of cholesterol ozonolysis products in human brains. These products and a related, lipid-derived aldehyde covalently modify Abeta, dramatically accelerating its amyloidogenesis in vitro, providing a possible chemical link between hypercholesterolemia, inflammation, atherosclerosis, and sporadic AD.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC387320 | biostudies-literature | 2004 Apr

REPOSITORIES: biostudies-literature

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Metabolite-initiated protein misfolding may trigger Alzheimer's disease.

Zhang Qinghai Q Powers Evan T ET Nieva Jorge J Huff Mary E ME Dendle Maria A MA Bieschke Jan J Glabe Charles G CG Eschenmoser Albert A Wentworth Paul P Lerner Richard A RA Kelly Jeffery W JW

Proceedings of the National Academy of Sciences of the United States of America 20040319 14

Anfinsen showed that a protein's fold is specified by its sequence. Although it is clear why mutant proteins form amyloid, it is harder to rationalize why a wild-type protein adopts a native conformation in most individuals, but it misfolds in a minority of others, in what should be a common extracellular environment. This discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease. One possibility is that an abnormal metabolite, generated only in some individu ...[more]

PMID: 15034169

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Project description:Numerous epidemiological studies have shown a significantly higher risk for development of Alzheimer's disease (AD) in patients affected by type 2 diabetes (T2D), but the molecular mechanism responsible for this association is presently unknown. Both diseases are considered protein misfolding disorders associated with the accumulation of protein aggregates; amyloid-beta (A?) and tau in the brain during AD, and islet amyloid polypeptide (IAPP) in pancreatic islets in T2D. Formation and accumulation of these proteins follows a seeding-nucleation model, where a misfolded aggregate or 'seed' promotes the rapid misfolding and aggregation of the native protein. Our underlying hypothesis is that misfolded IAPP produced in T2D potentiates AD pathology by cross-seeding A?, providing a molecular explanation for the link between these diseases. Here, we examined how misfolded IAPP affects A? aggregation and AD pathology in vitro and in vivo. We observed that addition of IAPP seeds accelerates A? aggregation in vitro in a seeding-like manner and the resulting fibrils are composed of both peptides. Transgenic animals expressing both human proteins exhibited exacerbated AD-like pathology compared with AD transgenic mice or AD transgenic animals with type 1 diabetes (T1D). Remarkably, IAPP colocalized with amyloid plaques in brain parenchymal deposits, suggesting that these peptides may directly interact and aggravate the disease. Furthermore, inoculation of pancreatic IAPP aggregates into the brains of AD transgenic mice resulted in more severe AD pathology and significantly greater memory impairments than untreated animals. These data provide a proof-of-concept for a new disease mechanism involving the interaction of misfolded proteins through cross-seeding events which may contribute to accelerate or exacerbate disease pathogenesis. Our findings could shed light on understanding the linkage between T2D and AD, two of the most prevalent protein misfolding disorders.

Dataset Information

Metabolite-initiated protein misfolding may trigger Alzheimer's disease.

Publications

Metabolite-initiated protein misfolding may trigger Alzheimer's disease.

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