Alzheimers Flashcards
how are amyloid diseases characterised?
Naturally occuring protein unfolds, misfolds, aggregates and collects into fibrous plaques
Disrupted ACh
Describe amyloid plaque structure
Formed from β-sheet protein and look similar in an x-ray beam
Form a cross every 4.7Å and 10Å at right angles, caused by parallel β-strands running at right angles
These pack into the same fibre
What is systematic amyloid disease?
Body producing excessive amounts of amyloid deposits in different tissue
What causes acute phase proteins to be produced?
Persistent chronic inflammation and builds and produces amyloid deposits in the kidney
How can dialysis lead to iatrogenic disease?
β2 microglobulin is a component of MHC Class I and builds up in organs and joints. Therefore β2 microglobulin was removed from dialysis mixture
Describe alzheimer’s disease
Accounts for 60-70% dementia
First symptoms are short term memory
Apathy, leading to withdrawal
After diagnosis, life expectancy is 3-9 years
Some genetic origins but incidence increases with age
Parts of the brain associated with language and memory die
Describe Aβ
40-42 residues made of APP.
TM and extracellular folded domain
How can alzheimers be treated?
Cholinesterase inhibitors- slow impairment of cholinergic neurons
NMDA glutamateric receptor agonist- prevents overstimulation of synapses.
Increasing α-secretase activity to decrease αβ
γ-secretase cleaves notch, so has effects all over the body unless targetted to the brain. Targetting the APP docking site, regulatory site or change where it cuts the C-terminus
How can NSAIDs be used to treat alzheimer’s?
Act as modulators and make γ-secretase change from αB(1-42) to αB(1-40)
What antibodies have been used to treat alzheimers?
Adceumab recognises amyloid aggregates and not Aβ monomers
No harmful effect, may work with high doses
What problems are associated with alzheimers drugs
Having multiple drug targets
Breaking down fibres to oligomers is toxic and makes it worse
How can the amyloid cascade be slowed?
Reduce cholesterol with statins
Tau kinases and tau aggregation inhibited so microtubules don’t stabilise
Why can alzheimer’s be considered type III diabetes?
Typre II produces inflammation and vascular damage to the brain, causing vascular dementia
What effect does Apo have on alzheimers?
ApoE2 is protective
ApoE4 is a risk factor. We don’t know why. May do something bad like make γ-secretase cut APP to make Aβ
Describe parkinson’s disease
Loss of physical and mental function
Shaking hands, rigidity in posture
Age related, more common in males
Affects dopamine
intrinsically disordered α-synuclein is the amyloid protein and collects in Lewy bodies in neurons
Symptoms apparent when 80% cells are dead
What are the genetic factors of parkinson’s disease
α-synuclein gene which organises presynaptic vesicles
LRRK2 gene involved in neurite outgrowth
TMEM230 which encodes a TM protein of secretory/recycling vesicles
What environmental factors are there to parkinson’s
Pesticides, head injury, metals
Why are intrinsically disordered proteins more likely to form aggregates
They do not need to unfold first so have a lower energy barrier
Describe kuru
Women ate brains of dead relatives, so kuru mainly spread in women
2% mortality
Almost eradicated due to can of cannibalism
Resistant allele G127V spread due to selective pressure. Caused a selective sweep
How does Aβ form?
APP is converted by presenilin to Aβ
Apolipoprotein E4 impairs Aβ clearance from the brain
The Ab oligomers phosphorylate tau which is neurotoxic
Describe the Ab variants
Aβ42 and 43 self-aggregate ajd Aβ40 is amyloidogenic
How might alzheimer’s be associated with Down’s syndrome?
APP gene is on chromosome 21 so individuals with down’s syndrome may produce too much Aβ lifelong, making them very susceptible to Alzheimer’s
What boosts protein aggregation?
Lipid bilayer interactions
pH changes in endosomes or lysosomes
Mutation/truncation of a polypeptide
How can IAPP damage lipid bilayers?
IAPP fibres elongate
β-sheet rich seed elongates, disrupting the bilayer
Accelarates primary nucleation of α-synuclein fibres
Describe secondary nucleation
Fibre fragmentation increases templating fibre ends which precursors are added to.
Fibre fragmentation increases endosomesand lysosomes taking up amyloid fibres
Local oligomer con increases
How can Aβ cause neurotoxicity?
Aβ can bind to mouse PirB or human ortholog LilrB2
This causes a signal cascade in neurons, hijacking the actin cytoskeleton and causing synaptic loss. Happens via receptor-ligand interaction
Why can Alzheimer’s e be considered type 3 diabetes?
Refer to word document
How can obesity be linked to alzheimer’s
Obesity is a risk factor for alzheimer’s and dementia as adipocytes secrete proteins, hormones and cytokines
Inflammation from this may cause vascular changes in the brain
How can nerve growth factor (NGF) be used as an alzheimer’s treatment?
Loss of NGF may contribute to loss of cholinergic neurons in AD
Crinical trials successful, e.g fibroblasts containing NGF-encoding viral vector implanted into AD patient forebrains
How is ApoE4 an alzheimer’s risk factor?
Cleavage of ApoE4 may give a truncated ApoE that impairs mitochondrial energy production and disrupt the cytoskeleton
How does lithium treat alzheimers?
It prevents tau phosphorylation
How can concentration of APP, tau and ApoE4 be lowered?
Small molecules or RNAi
