Neurodegenerative Diseases 20-21 PDF

www.healthcare.siemens.com/ www.alz.org Neurodegenerative Diseases Dr Sarah Trinder [email protected] Outline ▪ Neurodegenerative disease mechanisms ▪ Protein misfolding & aggregation ▪ Mechanisms of neuronal death ▪ Ischaemic brain damage (stroke) ▪ Alzheimer’s disease ▪ Parkinson’s disease Ne...

www.healthcare.siemens.com/ www.alz.org Neurodegenerative Diseases Dr Sarah Trinder [email protected] Outline ▪ Neurodegenerative disease mechanisms ▪ Protein misfolding & aggregation ▪ Mechanisms of neuronal death ▪ Ischaemic brain damage (stroke) ▪ Alzheimer’s disease ▪ Parkinson’s disease Neurodegenerative diseases ▪ Pathological process(es) causing neuronal damage/death ▪ Neurogenesis – formation of neurons from progenitor cells www.alz.org ▪ Pathological focus of lecture ▪ Ischaemic brain damage (stroke) – acute ▪ Alzheimer’s disease ▪ Parkinson’s disease chronic Principles to consider.... ▪ Protein misfolding & aggregation ▪ Chronic neurodegenerative disease ▪ Alzheimer’s & Parkinson’s disease ▪ Mechanisms of neuronal death ▪ Excitotoxicity ▪ Apoptosis ▪ Oxidative stress Protein folding ▪ Proteins folded to their 3D shape in ER ▪ √ folded proteins → golgi ▪ X folded proteins → ubiquniated Dobson, 2003, Nature, 426, 884-90 Protein misfolding & aggregation From Rang & Dale’s Pharmacology 8th Ed. Mechanisms of neuronal death ▪ Necrosis ▪ Due to acute injury ▪ Cell swells → Ca2+ overload & membrane damage → cell swelling → vacuolisation & lysis ▪ Spills contents of cell into surrounding tissue → inflammatory response ▪ Chronic inflammation - feature of neurodegenerative disease Syntichaki & Tavernarakis, 2003, Nat. Rev. Neurosci, 4, 672-84 Mechanisms of neuronal death ▪ Apoptosis ▪ Programmed cell death ▪ Essential mechanism ▪ Systematic dismantling of cell – activation of caspases ▪ Shrunken remnants removed by macrophages ▪ No inflammatory response ▪ Neuronal growth factor (NGF) & BDNF ↓apoptosis ▪ ↓Bax (pro-apoptotic) & ↑Bcl-2 (anti-apoptotic) Excitotoxcity ▪ Glu is highly toxic to neurons ▪ Ca2+ overload is an essential factor ▪ Raised [Ca2+] ▪ ↑Glu release ▪ ↑protease and lipase activation ▪ Activation of nNOS ▪ ↓[NO] neuroprotective, ↑[NO] + ROS = cell damage ▪ ↑arachidonic acid release - ↑ROS & ↓ Glu reuptake From Rang & Dale’s Pharmacology 8th Ed. Excitotoxicity ▪ Glu & Ca2+ stored in subcellular organelles ▪ Defences against Glu & Ca2+ overload ▪ Mitochondrial energy metabolism ▪ Impaired mitochondria ▪ Parkinson’s ▪ Stroke ▪ Superoxide dismutase (SOD) From Rang & Dale’s Pharmacology 8th Ed. Oxidative Stress ▪ Mitochondrial oxidative phosphorylation – generates ATP Ho et al, 2012, Transl. Neurodegenr, 1, 672-84 ▪ Excessive ROS production = oxidative stress ▪ NO synthesis, arachidonic acid metabolism ▪ Reperfusion – leukocytes release cytotoxic oxygen ▪ Damages DNA, enzymes & membrane lipids Oxidative Stress ▪ Defence mechanisms ▪ SOD, catalase, antioxidants, glutathione & vitamin E ▪ Oxidative stress – cause and consequence of inflammation ▪ Mitochondrial integrity essential for neuronal survival ▪ Mitochondrial respiratory chain enzyme mutations → congenital or age related ↑in susceptibility to oxidative stress ▪ Mitochondrial dysfunction key factor in many neurodegenerative diseases ▪ Damaged mitochondria → cytochrome c release → pro-apoptotic Ischaemic brain damage Ischaemic brain damage ▪ Stroke – 2nd most common cause of death globally (WHO, 2015) ▪ 70% of stroke non-fatal ▪ 85% of stroke are ischaemic ▪ Thrombosis/blockage of artery ▪ 15% haemorrhagic ▪ Rupture of a cerebral artery Neurosciencenews.com Ischaemic brain damage ▪ Interruption to blood supply → exocitotoxicity ▪ Central core – irreversible necrosis ▪ Reperfusion → production of ROS on restoration of O2 ▪ Takes hrs to develop – therapeutic opportunity? ▪ Penumbra surrounds core ▪ Inflammation & cell death Mehta SL, Vemuganti R (2014). Mechanisms of stroke induced neuronal death: multiple therapeutic opportunities. Adv. Anim. Vet. Sci. 2 (8): 438-446. Ischaemic brain damage - therapeutics ▪ Alteplase – plasminogen activator – disperses thrombus ▪ Did not reduce mortality – significant functional benefit ▪ Given within 3hrs ▪ Not in haemorrhagic stroke – why? ▪ CT scanning required ▪ Use is limited ▪ Surgery to remove clot/obstruction ▪ Future – neuroprotective agents – rescue cells in penumbral region? Alzheimer’s disease Alzheimer’s disease (AD) ▪ Loss of cognitive ability with age – normal ▪ AD – dementia that does not have a cause ▪ Stroke, brain trauma, alcohol ▪ Prevalence rises with age ▪ 5% at 65yrs to 90%+ at 95yrs ▪ Age-related dementia – accelerated neuronal loss ▪ Falling blood supply due to atherosclerosis? www.alz.org Alzheimer’s disease - pathogenesis ▪ Associated with brain shrinkage & localised loss of neurons ▪ Hippocampus & basal forebrain ▪ Loss of cholinergic neurons – hippocampus & frontal cortex http://ladulab.anat.uic.edu/ ▪ Underlie cognitive deficit & loss of short-term memory? ▪ Aggregates of misfolded proteins ▪ Extracellular amyloid plaques ▪ Amorphous extracellular deposits of β-amyloid protein (Aβ) ▪ Intraneuronal neurofibrillary tangles ▪ Filaments of phosphorylated Tau Intraneuronal neurofibrillary tangles http://thebrain.mcgill.ca/ Amyloid plaques ▪ Altered processing of amyloid protein from amyloid precursor protein (APP) ▪ Aβ40 & Aβ42 aggregate to form amyloid plaques ▪ Aβ42 strongly amyloidogenic ▪ Rare familial AD – mutations of APP gene ▪ Down’s syndrome – early AD-like dementia ▪ Overexpression of APP From Rang & Dale’s Pharmacology 8th Ed. Loss of cholinergic neurons Motor control Arousal - Alzheimer’s disease Learning & short term memory From Rang and Dale’s Pharmacology 8th Ed. Therapeutics ▪ No drugs to halt AD ▪ Cholinesterase inhibitors ▪ Tacrine – modest improvement in memory & cognitive tests – 40% of patients ▪ Take 4x daily! Side effects – monitor hepatoxicity, nausea, abdominal cramps ▪ Newer compounds – similar clinical effect, lower side effect profile ▪ Memantine – weak antagonist of NMDA ▪ Potential inhibitor of excitotoxicity ▪ Modest cognitive improvement, not neuroprotective Parkinson’s disease Parkinson’s disease ▪ Affects 1:500, ~127,000 in UK ▪ Progressive disorder of movement ▪ Suppression of voluntary movements – bradykinesia ▪ Walk with ‘shuffling gait’ ▪ Tremor at rest ▪ Variable degree of cognitive impairment ▪ Associated with dementia, depression & autonomic dysfunction ▪ Gene mutations? ▪ Leucine-rich repeat kinase 2 (LRRK2) ▪ Familial early onset – synucleun & parkin http://feinsteinneuroscience.org/ Neurochemical changes ▪ ↓DA in DAergic nigrostriatal pathway ▪