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- Amyloid; A Link to CH 3 Metabolism?

 Folate  B12.  SAM or  SAH. CH 3. C. DNA hypomethylation. G. Gene overexpression.  PS1= presenilin 1. Amyloid precursor protein. Amyloid . (BACE)  (PS1, PS2). secretases. Chan A, 2007, Fuso A, 2005 / scarpa S, 2003. - Amyloid; A Link to CH 3 Metabolism?.

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- Amyloid; A Link to CH 3 Metabolism?

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  1.  Folate  B12  SAM or  SAH CH3 C DNA hypomethylation G Gene overexpression  PS1= presenilin 1 Amyloid precursor protein Amyloid  • (BACE)  (PS1, PS2) secretases Chan A, 2007, Fuso A, 2005 / scarpa S, 2003 -Amyloid; A Link to CH3 Metabolism? Amyloid 

  2. 60 50 40 30 20 CSF SAM/SAH ratio 10 9 8 r=-0.31, p=0.001 7 6 5 100 200 300 400 600 800 1000 2000 CSF--amyloid (1-42), ng/L CSF- -amyloid (1-42)correlates to CSF-SAH and SAM/SAH 182 patients (multiple sclerosis, stroke, dementia, peripheral neuropathy, others) A lower methylation potential was associated withhigher P-tau and Amyloid-β concentrations in CSF

  3. Parkinson Pathophysiology Second most common neurodegenerative disease • Degeneration of dopaminergic neurons in the substantia nigra region of the brain (black substance) • Plays important role especially in control of movement • Neuronal cells of substantia nigra produce dopamin • Presence of intracellular inclusions: Lewy bodies and Lewy neurons that are rich of α-Synuclein • 15-25% of AD patients develop motor deficits with α-Synuclein rich Lewy body inclusions • α-Synuclein is an abundant synaptic protein • It is a 140 amino acid peptide; present in the presynaptic terminals of neuronal cells • Exact physiological role of α-Synuclein is not known • α-Synuclein is believed to modulate neurotransmitter release (ER/Golgi trafficking) • It is loosely associated with synaptic vesicles • Interaction of amyloid-β and α-Synuclein in brains with Lewy bodies has been found • Accumulation of both in Lewy bodies suggests mutual pathologic conditions

  4. Lipids/phospholipids Interact and inhibits - Phospholipase D2 a-Synuclein positive extracellular Lewy body Phosphatidyl- choline Pigmented nerve cell containing an a-synuclein- positive Lewy body Pigmented nerve cell with a-synuclein-positive Lewy bodies Choline + Posphatidic acid Phospholipids metabolism Dopamin release -Synuclein 140 AA fibrus multimer monomer natively unfolded Vesicular transport of neurotransmitters Molecular Chaperon ER/Golgy transport folding and refolding of synaptic proteins Transient association with Presynaptic vesicles vesicle Vesicular release and turnover

  5. + - PIMT + - +  Folate, B12 HHCY  Amyloid   SAM/SAH  PS1 monomer Oxidative stress  -Synuclein Phosphorylation/nitration Homocysteinylation Glycation D-aspartyl, L-isoaspartyl  -Synuclein UPS (20S) Unfolded protein can not be removed Lysosomal degradation polymer fibrus PIMT; Protein D-aspartyl, L-isoaspartyl O-methyltransferase UPS; ubiquitin proteasome system

  6. 80 R=-0.29, p=0.05, n=45 60 Platelets -Synuclein, ng/mL 40 20 0 50 100 150 200 250 S-adenosyl methionine, nmol/L Markers of neurodegenration are related to plasma SAM in PD patients Study included 90 patients with PD (mean age 68 years) -Synucleine was measured in platelats ectract

  7. R=0.42, p=0.005, n=45 35 32 30 28 Plasma amyloid beta, pg/ml 25 22 0 20 40 60 Platelets-synuclein, ng/ml Plasma amyloid- is related to markers of neurodegenration in platelets Study included 90 patients with PD (mean age 68 years) Platelets APP, -synuclein adjusted for cell proteins

  8. PD not treatd L-Dopa plus COMT inhibitor L-Dopa Higher plasma beta amyloid predicts lower cognitive function scores 35 R=-0.45, p>0.001, n=71 32.5 • The MMSE tests: • Orientation (max. 10 pts) • Immediate Recall (max.3 pts) • Attention and calculation (max. 5 pts) • Recall (max. 3 pts) • Language (max. 9 pts) • 23-30 = Normal, • 19-23 = Borderline • <19 = Impaired 30 Plasma Amyloid beta, pg/ml 27.5 25 22.5 17.5 20 22.5 25 27.5 30 MMSE, scores

  9. Higher plasma -amyloid predicts lower cognitive function scores PD not treatd 35 L-Dopa plus COMT inhibitor R=-0.45, p>0.001, n=71 L-Dopa 32 • α-synuclein a new marker of neuronal degeneration in PD correlated inversely with SAM but positively with amyloid-β • In patients with PD the cognitive scores correlated directly with the methylation potential but inversely with amyloid-β 30 Plasma Amyloid beta, pg/ml 28 25 22 0 5 10 15 20 DemTect, scores PD patients, n=71

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