Alzheimer's disease pathophysiology Flashcards
What changes can happen in the brain in AD?
- Atrophy (decline/decrease) in the cerebral cortex and hippocampus by 15-20%
- Sulci widened (groove in the cerebral cortex) = bigger gaps = decreased surface area = decreased grey matter and leads to neuronal cell loss.
- Formation of extracellular plaques between cells that contain β-amyloid peptide = missfolding and aggregation of proteins is considered pathogenic in many neurodegenerative conditions.
- Formation of intra-neuronal neurofibrillary tangles composed of hyperphosphorylated tau protein
- Functional losses in neurotransmitters- loss in cholinergic, GABAergic, monoaminergic transmitter systems
Where do the first changes in the brain occur?
In the hippocampus and the frontal cortex = these occur pre-clinically (before symptoms present). Overtime, Changs spread to over most of the brain.
How is β- amyloid produced?
β-amyloid is a 36-43 amino acid peptide is produced from the amyloid precursor protein (APP) by the action of secretases
What is APP?
Amyloid precursor protein- a large transmembrane glycoprotein (77 aa) found in many cells.
Cleavage of APP gives roles in:
Transcriptional regulation
Growth factor function
Synaptic transmission
What are the different enzymes that cleave APP (Amyloid precursor protein)?
𝛼-secretases
β-secretases
𝜸-secreteases
What is the process of B-amyloid production
APP is cleaved by alpha-secretase and the EC part forms soluble APP (SAPP)
This remainder of the protein can be cleaved by gamma-secretase within the transmembrane domain.
Cleavage by beta and gamma secretase leads to production of β-amyloid which is toxic ( the protein found between beta and gamma cleavage sites).
- Beta-amyloid forms plaques- Aβ40 and Aβ42
Aβ40 is most abundant
Aβ42 is more likely to form plaques though- as is insoluble and amyloidogenic
- mutations in APP affected where secretases can cut and so increase the proportion of Aβ42 = increased plauques
- Mutations in presenillin- the catalytic part of the 𝜸-secretase complex = increased 𝜸-secretease activity = increased β-amyloid plaques
What are the two types of beta-amyloid formed?
Aβ40 and Aβ42
Aβ40 is most abundant (80-90%)
Aβ42 is more likely to form plaques (10-20%)
How are the β-amyloid plaques deposited and what do they cause?
The β-amyloid monomers combine to form oligomers. Oligomers combine to form fibrils.
Fibrils go on to form amyloid-β-plaques (these plaques also contain: microglia, astrocytes, apolipoproteins)
Soluble Aβ ogliomers:
- These are disruptive to signalling through the NMDA receptor = synaptic dysfunction
- Disrupts Long term potentiation (LTP) associated with memory
- They can cause neuronal cell death
Plaque-associated protein (apolipoproteins etc) incorporated into fibril to produce extracellular plaque:
- Can cause direct cytotoxic effects in neurones
- Also, initiate an inflammatory response: microglia activation = cytokine release = leads to mitochondrial damage and oxidative stress = neuronal cell death
What is the effect of neurofibrillary tangles on pathology of AD?
These neurofibrillary tangles are formed from hyperposphorylated Tau protein.
Normally Tau:
- involved in stabilisation of microtubules = important in axonal transport from one end of neurone to the other
- It binds to microtubules to stabilise them, then when TAU is phosphorylated, Tau is detached and dephosphorylation of microtubules occurs.
BUT, if TAU is hyperphosphorylated, it is no longer attatched to the microtubule and instead aggregates to form paired helical filaments. These lead to formation of neurofibrillary tangles = microtubules depolymerise = loss of axonal transport = neuronal cell death.
What is the effect of changes in neurotransmitters on the pathology of AD?
Most important is the changes to the cholinergic pathways which are widely distributed.
Acetylcholine is involved in discrete pathways:
- Cell bodies in the nucleus basalis project their axons to the cortex and synapse with cortical neurones
- Septical nucleus project to the hippocampus- role in memory
- Brainstem ti the thalamus- involved in motor control
- Cholinergic interneurones in the striatum- involved in motor control
- Ach has roles in arrousal (wakeness) and reward pathways- involves nicotinic receptors, hence why nicotine is so addictive as it also acts at the acetylcholine receptors
- In AD, the frist 2 pathways above are most affected hence the decrease in memory and cognition in AD
What is the effect of neurochemical changes in the brain on the pathology of AD?
- Post-mortem brain tissue has shown a loss of cholinergic neurones in the basal forebrain ( nucleus basalis to cortex) and hippocampus ( from septal nucleus) = decreased cognition, learning and memory.
- Reduced choline acetyltransferase activity (50-90% decrease)- responsible for making Act
Also, there is a decrease in Acetylcholine esterase, choline transport and nicotinic receptor density in the cortex = all lead to decrease Ach concs
Why do people with Down syndrome have an increased risk of AD?
Downs syndrome predisposes a patient to AD as the Amyloid precursor protein is located on chromosome 21. DS has 3 copies of this chromosome and so there is a higher expression of APP = more β-amyloid = increased plaque formation that leads to AD.
What are some mutations that can cause early onset AD?
- APP (amyloid precursor protein)- mutations tend to occur at the cleavage sites of β and 𝜸 secretase- meaning cleavage occurs at the wrong positions, that favours Aβ42- This is more amyloidogenic = more plaques
- Mutations in presenilin genes (PSEN1 & PSEN2): This is a transmembrane protein that regulates the catalytic part of 𝜸-secretase. Mutations here, lead to an increase in Aβ42 and therefore increased plaque formation. This is the most common mutation seen in early-onset AD
- TAU mutations- leads to increased phosphorylation of TAU.
What is early-onset AD?
This is AD that presents younger than 60 years old- accounts for 5% of AD cases.
What is the genetic basis of late-onset AD?
Mutations in the APOE gene- a lipid-binding lipoprotein involved in transport of lipids. Also, Apolipoprotein is found in the plaques and is thought to have a role in plaque clearance- APOE4 is less effective at clearing these plaques.
- There are 4 variants of this gene- 1,2,3 and 4.
We inherit 1 allele from our mother and 1 allele from our father
APOE-4 is strongly linked to AD- so inheriting 2 APOE4 alleles (apoe4 from both mother and father) = increased incidence of AD
- APOE2 shoes the lowest risk
