Biochem post-midterm- AZ disease

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komail
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253309
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Biochem post-midterm- AZ disease
Updated:
2013-12-15 15:42:57
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biochem
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biochem
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  1. Characteristics of AD
    Neurofibrillary tangles (Tau aggregations) and intraneural accumulation of B-amyloid plaques (AB-oligomer aggregates)

    Lack of calcium regulation
  2. What happens when Ca levels are consisently high
    • Protein Kinase C is activated by Increased Calcium 
    • Calpain (cysteine protease) activated by increased Calcium (targets cell cytoskeleton leading to cell death)
  3. Why might tau be overphosphorylated?
    Over-activation of Protein Kinase C, which hyperphosphorylates tau
  4. Where are the localized regions of damage in AD?
    • hippocampus (learning and memory) shows an increase in plaques and NFT
    • cholinergic neurons are damaged (low levels of ACh seen; cholinesterase inhibitors and organophosphates are sometimes used to treat)
  5. B-amyloid
    40-42 amino acid peptide which olgomerizes and forms neuritic plaques

    created by sequential cleavage of APP (300+ a.a.)

    Inhibits activity of mt complex 2 and 4 (decreased ATP and increased ROS) as well as a-ketoglutodehydrogenase, AB-alcohol dehydrogenase, and cyclophillin D expression

    enhances impairment of Ca2+ homeostasis+ impairment of's Ca 2+ handling ability-> enhances MPT pore opening+ cyt C release leading to apoptosis/necrosis
  6. APP
    300+a.a.

    • alters Ca2+ homeostasis (leads to apoptosis)
    • can bind directly to mt as well (increased ROS)
  7. What can phosphorylated tau and AB cause that leads to neural degeneration
    Increased fission
  8. AB and APP cause reduced expression of _____
    • PGC-1a, leading to increased neurodegeneration 
    • (a PPAR-y agonist, like resveratrol, reduces AB induced mitochondrial dysfunction and neurodegeneration
  9. Mt localization of AB, impaired mt dynamics and trafficking in AD
    • Increased autophagic degradation of mt in AD
    • altered balance of fusion/fission
    • Since energy consumption is highest at synapses, synaptic mitochondria are more susceptible to AB induced mt dysfunction

    AB binds directly to AB-alcohol dehydrogenase, and the mt/mt proteins (increasing toxicity)

    APP affects mitochondrial importa channels (possibly altering Ca2+ regulation)
  10. mtDNA encoded defects in AD
    • cybrid cell lines with mtDNA from AD patients, how same pathology and phenotype observed in AD. i.e.
    • -reduced mitochondrial movement
    • reduced MMP
    • altered morphology
    • synaptic degeneration
  11. Creatine
    • involved in energy supply to muscle and nerve cells 
    • creatine->phosphocreatine (enzyme: creatine kinase) in neurons+muscle

    creatine neuroprotective in animal models of PD, AD, ALS, and protects against MPP+ damage. 

    Creatine further protects from PD is administered with nicotinamide (Cox-2 inhib), or if administered with CoQ10
  12. Clinical trials with creatine in PD
    beneficial affectson patient's mood, but no alteration on the unified parkinson's disease rating scale scores

    enhanced endurance, and upper body strength

    seems promising
  13. CoEnzyme Q10
    endogenous biological substrate for ETC, and anti-oxidant in mt

    • protects DA neurons against MPTP
    • reduces mitochondrial dysfunction
    • reduced a-synuclein aggregation

    cominbation with creatine provides additive benefits
  14. Clinical Trials with CoQ10in PD
    • Dose dependent decrease in UPDRS (good thing)
    • Betterment of motor symptoms
  15. MitoQ and mitochondrial targetted peptides
    MitoQ (co-enzyme Q ubiquinone covalently linked to trphosphonium ions, which confers selectivity for mt)

    Protects against AB impairments in AD models, no improvement in UPDRS scores though

    • Mitochondria targetted peptide SS= synthetic tetrapeptides that selectively localize to inner mt membrane
    • decreased ROS in mt
    • inhibit mt swelling, reducing cyt C release
    • showed neuroprotection in MPTP model of PD, decreased ROS

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