Pathogenesis of dementia Flashcards
List three major neurodegenerative diseases associated with abnormal protein conformations?
Azheimer’s disease
Creutzfeldt-Jakob disease
Parkinson’s disease
Describe the genetic risk factors for Alzheimer’s disease?
Chromosome 21 (APP mutations)
Chromosome 19 (Apolipoprotein E)
Chromosome 14 (PS 1)
Chromosome 1 (PS 2)
Down’s syndrome (trisomy 21)
Describe the environmental risk factors for developing Alzheimer’s disease?
Which has a larger impact on the development of AD: genetic or environmental risk factors?
Genetic factors
Describe the four basic types of AD?
Amnestic (temporal)
Visuospatial (R>L)
Aphasic (L>R)
Frontal
What are the two major pathologic lesions in the brain in AD?
Amyloid-beta plaques
Neurofibrillary tangles
Describe how amyloid-beta plaques form in AD?
How do neurofibrillary tangles form in AD?
Aggregation of tau, thought to be driven by amyloid beta peptide
Which part of the amyloid protein is thought to induce the pathogenesis of AD?
After short peptode released from TM domain, reforms as tetramer or dimer
These oligomers get stuck on or near synapses and interfere with normal processes of transmission, leading to degeneration
Describe one approach to taregtting the Ab oligomer in treating AD?
MPAC
Metal-protein attenuating compound
Small proteins that can cross BBB and cause compete with metals for binding sites on Ab dimers > dimers fall apart and can be processed
Describe the current approach to diagnosing AD?
1) Measuring Ab peptide in CSF
2) Radiolabelled ligand which binds amyloid filaments > PET scan
Describe how Ab levels vary in Alzhemier’s compared to health controls?
AD patients sit above arbitrary cutoff of 1.5
However, lots of healthy controls and patients with MCI also sit above this cutoff > are on their way to developing AD
Describe the progression of Ab deposition over time?
Takes thirty years to move from completely normal to full blown AD
Takes 20 years to move from 1.5 cutoff to full blown AD
Within which category of diseases does Creutzfeldt-Jakob disease belong?
Transmissible Spongiform Encephalopathies
What is the natural host of CJD?
Humans
In which countries does CJD occur?
At what rate?
Sporadically all around the world
1 in 1 million
What is kuru characterised by?
Tremors and shaking
Cerebellar degeneration
Briefly describe how kuru was acquired?
Infectious disease
Women and children exposed when they dismembered dead bodies
Describe the similarirties in causes between kuru and BSE?
Kuru: feeding humans to humans
BSE: feeding cattle to cattle
Both due to cannabilism
Describe the histological appearrance of brains affected by BSE?
Vacuoles developing within neuropil
Fluid filled, membrane bound bound holes sitting in the cells of neurons
Many astrocytes reacting to damage to nerve cells
Which molecule is responsible for the development of BSE?
How does it differ to normal?
PrPres (prion protein)
Has beta pleated sheet, which makes it insoluble and resistant to degradation
Has ability to induce normal form (PrPc) to take on same shape
What is vCJD?
Variant CJD
New form of human BSE affecting young individuals after infected BSE carcasses entered human food supply
Presented in form similar to kuru - cerebellar predominance, neuropsychiatric phenomena
Why are people who lived in the UK (in specified period) prohibited from donating blood?
vCJD blood is infectious
Estimated incubation period is 6-15 years > peak exposure of BSE was in 1988-1993 > blood infectivity now at peak
Describe the brain area affected by PD?
Dopaminergic neurons in substantia nigra
Which molecule, other than DA, has been implicated in the development of PD?
a-synuclein
Describe the molecular pathway which underlies PD?
a-synuclein comes into contact with Da > becomes redox active > combination induces a-synuclein to fold abnormally > becomes insoluble
Lewy Body inclusions
