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Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases.

PloS one | Sep 4, 2008

BACKGROUND: Misfolding and pathological aggregation of neuronal proteins has been proposed to play a critical role in the pathogenesis of neurodegenerative disorders. Alzheimer's disease (AD) and Parkinson's disease (PD) are frequent neurodegenerative diseases of the aging population. While progressive accumulation of amyloid beta protein (Abeta) oligomers has been identified as one of the central toxic events in AD, accumulation of alpha-synuclein (alpha-syn) resulting in the formation of oligomers and protofibrils has been linked to PD and Lewy body Disease (LBD). We have recently shown that Abeta promotes alpha-syn aggregation and toxic conversion in vivo, suggesting that abnormal interactions between misfolded proteins might contribute to disease pathogenesis. However the molecular characteristics and consequences of these interactions are not completely clear. METHODOLOGY/PRINCIPAL FINDINGS: In order to understand the molecular mechanisms involved in potential Abeta/alpha-syn interactions, immunoblot, molecular modeling, and in vitro studies with alpha-syn and Abeta were performed. We showed in vivo in the brains of patients with AD/PD and in transgenic mice, Abeta and alpha-synuclein co-immunoprecipitate and form complexes. Molecular modeling and simulations showed that Abeta binds alpha-syn monomers, homodimers, and trimers, forming hybrid ring-like pentamers. Interactions occurred between the N-terminus of Abeta and the N-terminus and C-terminus of alpha-syn. Interacting alpha-syn and Abeta dimers that dock on the membrane incorporated additional alpha-syn molecules, leading to the formation of more stable pentamers and hexamers that adopt a ring-like structure. Consistent with the simulations, under in vitro cell-free conditions, Abeta interacted with alpha-syn, forming hybrid pore-like oligomers. Moreover, cells expressing alpha-syn and treated with Abeta displayed increased current amplitudes and calcium influx consistent with the formation of cation channels. CONCLUSION/SIGNIFICANCE: These results support the contention that Abeta directly interacts with alpha-syn and stabilized the formation of hybrid nanopores that alter neuronal activity and might contribute to the mechanisms of neurodegeneration in AD and PD. The broader implications of such hybrid interactions might be important to the pathogenesis of other disorders of protein misfolding.

Pubmed ID: 18769546 RIS Download

Mesh terms: Alzheimer Disease | Animals | Brain | Calcium | Computer Simulation | Electrophysiology | Humans | Lewy Body Disease | Mice | Mice, Transgenic | Parkinson Disease | Protein Denaturation | Protein Folding | Protein Structure, Tertiary | alpha-Synuclein

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Associated grants

  • Agency: NHLBI NIH HHS, Id: HL066012
  • Agency: NIA NIH HHS, Id: R01 AG018440
  • Agency: NIA NIH HHS, Id: R37 AG018440
  • Agency: NIA NIH HHS, Id: AG18440
  • Agency: NHLBI NIH HHS, Id: R01 HL066012

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Alzheimer's and Dementia Resource Center

The Alzheimer's and Dementia Resource Center (ADRC) facilitates tissue donations for the Brain Bank Research Program in order to help find better treatments, more diagnostic tools and a cure for Alzheimer's disease and dementia. The Brain Bank Program is administered by Mount Sinai Medical Center in Miami Beach and under contract with the Florida Department of Elder Affairs. ADRC also provides caregivers with the educational resources, spiritual comfort and emotional support. The ADRC facilitates training for professional caregivers that meets requirements for the Florida Department of Elder Affairs.


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