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komail
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Characteristics of AD
Neurofibrillary tangles (Tau aggregations) and intraneural accumulation of B-amyloid plaques (AB-oligomer aggregates)
Lack of calcium regulation
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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)
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Why might tau be overphosphorylated?
Over-activation of Protein Kinase C, which hyperphosphorylates tau
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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)
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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
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APP
300+a.a.
- alters Ca2+ homeostasis (leads to apoptosis)
- can bind directly to mt as well (increased ROS)
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What can phosphorylated tau and AB cause that leads to neural degeneration
Increased fission
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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
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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)
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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
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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
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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
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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
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Clinical Trials with CoQ10in PD
- Dose dependent decrease in UPDRS (good thing)
- Betterment of motor symptoms
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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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