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MCSA Journal Club January 2019

MCSA Journal Club January 2019. Presented by: Peter Kunach. β -Amyloid peptides enhance a-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease.

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MCSA Journal Club January 2019

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  1. MCSA Journal ClubJanuary 2019 Presented by: Peter Kunach

  2. β-Amyloid peptides enhance a-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer’s disease and Parkinson’s disease Eliezer Masliah, Edward Rockenstein, Isaac Veinbergs, Yutaka Sagara, Margaret Mallory, Makoto Hashimoto, and Lennart Mucke

  3. Introduction • Alzheimer’s disease and Parkinson’s disease are associated with the cerebral accumulation of β-amyloid and a-synuclein, respectively. • Some patients have clinical and pathological features of both diseases, raising the possibility of an overlapping neuropathological phenomena. Hypothesis: Does hSYN and Ab interact more directly by engaging synergistic neurodegenerative pathways? To answer this question, the researchers generated a transgenic mouse model with neuronal expression of human β-amyloid peptides and a-synuclein.

  4. Methods • Generation of Tg Mice: HemizygousehSYN x Hemizygous hAPP(sw and in); • Behavioural Testing: Rotarod and Morris Water Maze; • Quantification of Transgene Products: • mRNA – Rnase Protection Assay; • Protein – Western Blot; • Aβ – ELISA; • Aβ1-40/ Aβ1-42 – Sandwich ELISA. • Neuronal Cell Culture: Immortalized hypothalamic neuronal cells transfected hSYN cDNA; • Neuropathological Analysis: Immunohistochemistry.

  5. Results – Quantification of Transgenes - mRNA

  6. Results – Quantification of Transgenes - Protein

  7. Results – Neuropathological – Cholinergic Neurons

  8. Results – Neuropathological – Neuronal Inclusions

  9. Results – Neuropathological – Aβ/hSYN Transfected Control Plasmid Exposed to 1-42 Untreated Exposed to 1-40

  10. Results – Behavioural - Rotarod

  11. Results – Behavioural – Morris Water Maze

  12. Conclusion • hSYN/hAPP mice show cognitive deficits and motor dysfunction, loss of cholinergic neurons, overexpression of amyloid, and intraneuronal a-synuclein inclusions. • These findings indicate that hSYN may enhance the plaque-independent neurotoxicity of Ab. • Overexpression of hAPP/Ab, promotes the intraneuronal accumulation of hSYN and accelerated the development of motor deficits in tg mice. In vitro studies strongly suggest that Ab1–42 is the predominant culprit.

  13. Conclusion cont. These features characterize AD with Lewy Body pathology and considering the number of patients with AD that develop clinical symptoms related to PD (Bradykinesia and resting tremor) and patients with PD that develop dementia, this study seems especially relevant.

  14. Notes • Direct effect of abeta and asyn on neuronal deficits? • In either case, the pathogenic interactions between Ab and hSYN demonstrated here suggest that drugs aimed at blocking the accumulation of Ab or hSYN might benefit a broader spectrum of neurodegenerative disorders than previously anticipated. • Since the acceptance of the paper, two reports have appeared demonstrating that Ab1-42 promotes the aggregation of tau into neurofibrillary tangles. These results are consistent with the effects of Ab1-42 on a-synuclein aggregation we identified in the current study. Taken together, these findings suggest that Ab1-42 might contribute to diverse conformational diseases.

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