53 - Pathogenesis of Dementia Flashcards
Abnormal gene product associated with Parkinson’s
Alpha synuclein
Age risk factor for Alzheimer’s after 50 years
Exponential doubling prevalence of Alzheimer’s with each decade after 50 years
Genes associated with increased Alzheimer’s disease risk
Apolipoprotein E
Presenilin 1
Presenilin 2
APP mutations
Chromosomal defect associated with Alzheimer’s
Trisomy 21.
Invariably get early-onset Alzheimer’s
Examples of risk factors for Alzheimer’s
Under seven years of education Head trauma Smoking Vascular disease Diabetes Antioxidants.
All of these give marginal increases in risk. Still don’t know major environmental risks for Alzheimer’s
Four basic types of Alzheimers
1) Amnestic (most common)
2) Visuospatial (affects right more than left)
3) Aphasic (affects left more than right)
4) Frontal
Where does Alzheimer’s often begin?
Temporal lobes, then spreads
What is APP?
Precursor protein, which is cleaved to form amyloid beta.
Neurofibrillary tangles
Aggregates of tau, a microfilament-associated protein
What do presenilin 1 and 2 affect?
Formation of APP
What do ApoE mutations affect?
How amyloid beta is cleared from brain
Possible cleavages of amyloid beta
Can be cleaved in the transmembrane domain, which leads to non-amyloidogenic pathway.
Can be cleaved in extracellular domain to form amyloid beta monomers, which aggregate into plaques.
Cellular components which cleave Abeta
Presenillin 1 and 2, with two other proteins.
Form a protein involved in proteolytic cleavage
What does Abeta do that can cause neurodegeneration?
Oligomer attaches to plasma membrane, interferes with synaptic transmission.
With age, oligomers aren’t cleared effectively, allowing buildup
Metal-protein attenuating compound
Small molecule that interferes with ability of amyloid beta to form oligomers.
How can Abeta be imaged in vivo?
Inject radio-labelled small molecules (carbon-11 Pittsburgh Compound B) that can bind to amyloid in brain.
This can be visualised with CT
How long does it take, roughly, from detectable levels of Abeta to complete Alzheimer’s?
~20 years
MAb administered against amyloid (in development)
Solanezumab
Effects of Solanezumab
Disease-modifying, not just symptom-modifying
Incidence of CJB in Australia
~1/1,000,000
How long can it take between exposure to infectious prions and manifestation of disease?
Several decades
What lead to the bovine spongiform encephalopathy epidemic in the UK?
Feeding dead cattle to other cattle.
Change in the brains of those with spongiform prion diseases
Small vacuoles in brain tissue (hence ‘spongiform’).
Characteristic of toxic challenge to neurons.
Molecular process of CJD
Conversion of cellular prion protein (PrPc) to PrPres.
Alpha helices in PrPc change conformation to beta sheets, forming PrPres.
PrPres can catalyse PrPc conformation change to PrPres, hence infectiousness.
Pathogenic mutations in PrP
Methionine mutations instead of a valine (homozygous) puts one at much greater risk of conversion from PrPc to PrPres
Difference between sporadic CJD (sCJD) and CJD from eating infected meat (cows infected with BSE) (vCJD)
Higher replication of PrPres in tonsils and lymphatic tissues.
Makes it more transmissible though blood
Where is alpha-synuclein expressed in the brain?
All synaptic membranes, helps vesicles dock onto internal surface of plasma membrane to release neurotransmitters
histological appearance of alpha-synuclein aggregates
Lewy bodies in substantia nigra
How is alpha-synuclein thought to aggregate?
In the presence of metals or dopamine, are induced to form oligomers, which then assemble into fibrils.
