Neurodegenerative disorders Flashcards
prevalence of alzheimers disease (AD):
- worldwide cost of US $818 billion
- by 2018, cost above US$ trillion
AD treatments: usually agonist/antagonist and con
- cholinergic agonist
- NMDA antagonist
- only symptomatic (doesn’t reverse slow course of disease)
AD: clinical definition
- presence of early and sig episodic memory impairment (isolated/associated) w other cognitive or behavioural changes that are suggestive of mild cognitive impairment or of a dementia syndrome incl etc..
AD: 2 classifications
- early onset AD (EOAD) <65yrs
- late onset AD (LOAD) >65yrs
AD: list 3 specific classifications
- sporadic EOAD
- familial EAOD
- autosomal dominant AD
AD: affected brain regions (3)
- damaged cortex (thinking, memory, planning)
- shrinkage: esp hippocampus (formation of new memories)
- increased ventricle size
AD: pathology
- plaques and tangles increases w severity of dementia
- ß amyloid
- tau
AD: genetic component- types (4)
- sAPPå (non-amyloidogenic)
- Aß (amyloidogenic)
- APP
- AICD
AD: amyloid hypothesis- 1960s
- plaques + tangles correlate to dementia
AD: amyloid hypothesis- 1985
- plaques composed of 42aa protein (Aß)
AD: amyloid hypothesis- 1987-90s
- precursor gene APP for Aß has mutations linked to some EOAD cases
AD: amyloid hypothesis- 1990s
- mutations in proteins that cleave APP (PSEN1, PSEN2) cause some EOAD cases
AD: amyloid hypothesis- latest discoveries (3)
- Aß toxic to cells in cultures
- mouse models created that over-express Aß
- removing Aß in these models prevents cognitive decline
AD: clinical trials- failure rate
99.6%
AD: clinical trials- possible reasons they are failing?
- perhaps treatment starting too late?
- treatment not reaching brain regions affected?
- disease cascade wrong
AD: alternaive pathological hallmarks (3)
- neuronal cell loss
- hyperphosphorylated tau
- neuroinflammation synapse loss
AD: J20 mouse model of alzheimer’s disease- features
- insertion of hAPP w 2 mutations
- plaque onset by 7 months
- minimal characterisation
AD: J20 mouse model of alzheimer’s disease- location and results
- hippocampus
- increase in oligomeric Aß and Aß plaques
AD: stereological cell counting technique
- using special square cells that touch the green side/ inside the box are counted
- those outside or touching red dismissed
which comes first: neuronal loss or plaque formation?
- neuronal loss precedes plaque formation
AD 1º research: microglia populations increase/decrease in AD progression
increase
AD 1º research: astrocyte pop during AD progression?
will plateau
AD 1º research: anxiety and locomotion? J20 mouse model
- in J20 mouse model
- decreased anxiety
- increased locomotion
AD 1º research: spatial memory and learning in J20 mouse model?
- deficits in both
AD 1º research: summary why treating amyloid may be too late in disease
- alternate pathological hallmarks of AD can occur earlier than plaque load in AD mouse model
AD 1º research II: can blocking AMPA receptors improve memory + learning? and summary
- yes
- treating neuroinflammation or neuronal cell loss may provide better target for halting disease cascade
MND: general features
- lour gehrig
- amyotrophic lateral sclerosis (ALS)
- 3-5yr life span from symptom onset
MND: upper motor neuron signs (6)
- increased tone
- hyper reflexia
- extensor plantar responses
- spastic gait
- exaggerated jaw-jerk
- slowed movements
MND: lower motor neuron signs (4)
- mm wasting
- weakness
- fasciculations
- absent/reduced deep tendon reflexes
MND: amyotrophic lateral sclerosis (ALS) signs
- combo of both upper and lower motor neuron signs
MND: multifaceted approach to diagnosis list (6)
- history
- neuroimaging
- physical examination
- electrodiagnostic studies
- lab testing
- genetic testing
MND: pathological perspective- list (5)
- spinal cord white matter atrophy
- loss motor neurons (ant horn SC, motor cortex of brain)
- ubiquitin-positive inclusions in neurons, frontal cortex, temporal cortex, hippocampus + striatum
- TDP-43 main component of ubiquitinated inclusions (ALS and FTD patients)
- neuroinflammation in motor cortex and SC
MND: % sporadic and familial
- sporadic 90%
- familial ~10%
MND: current treatments (2)
- riluzole
- edaravone
MND: mouse model- drugs on grip strength and survival
- no improvement of strength
- no better survival
MND: mouse model- neuroinflammation indicators 2wks? before neuron loss
- 16 genes are upregulated
MND: mouse model- neuroinflammation indicators 4wks? during neuron loss
- 14 upregulated
- 1 gene downregulated
MND: mouse model- CXCL10 protein levels
- 11x increase of protein expression in brain
MND: mouse model- CXCL10 protein role in TDP43 rats and location
- upregulation of astrocytes
- spinal cord
MND: mouse model- CXCL10 expression how?
tissue/cell - protein - 1º antibody - 2º antibody - fluorescein
MND: mouse model- TDP43 mouse inflammatory markers
- very similar to humans
- 9/13
conclusion: 6 Qs
- humans?
- mechanism?
- help/hindrance?
- best model?
- therapeutic target?
- biomarker?
current project 1: can reducing CXCL10 rescue mouse phenotype?
- GLUT1 to enhance BBB crossing
current project 2: can we model MND in more specific way?
- AAV injection of mutated TDP43
- visualise in SC
- grip strength
AD vs NMD? similarities and diff (5)
- neurodegeneration (diff areas)
- neuroinflammation
- pathology overlap?
- proteins NOT disease driver?
- v diff clinical signs
