Pathology of nerves system Alzheimer's disease
35 important questions on Pathology of nerves system Alzheimer's disease
What is the most prevalent form of dementia?
- sporadic progressive neurodegenerative disorder
- familial case: < 0.1%
- prevalance NL: 250.000
- incidence: 10.000-20.000
What are some characteristics of Alzheimers's?
- Memory disturbances
- language problems
- problems with praxis
- problems with visual recognition
- disturbances in executive functions
- disorientation
- psychosis
- depression, hallucination
Alzheimer's disease metabolism: which proteins are abnormally folded?
Amyloid beta protein
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How does Tau fosforylation work?
- Tau is a protein that bind to microtubuli and stabilizes them
- Tau in Alzheimer brains is hyper-fosforylated
Why do we see neurofibrillary tangles in AD?
- Hyperphosphorylation by kinases
- dephospho rylation normally through phosphates
- in AD: decreased activity phosphatases
Tau protein in Alzheimer's disease
- Healthy area: microtubules organized
- Diseased area: microtubules collapse
- Essential metabolites cannot be transported
- Neuronal loss
Amyloid Beta (AB) protein and Non-amyloidgenic pathway
- Cleavage with B- and Y-secretase
- three cleavage products:
- sAPPB
- Amyloid B
- C99
B = Beta
APP processin: B-secretase and a-secreatase
- BACE-1 (Beta-Site-APP-Cleaving Enzyme)
- BACE-2; homologue of BACE-1; almost no expression in the brain
- BACE-1 knock-out mice do not produce AB (amyloid beta)
a-secretase enzymes
- ADAM-10 (A disintergrin and Metalloproteinase)
- TACE (Tumour necrosis factor-Alpha Convertase)
APP processing: y-secretase
- presenilin (Psn)
- Nicastrin (Nct)
- Anterio pharynx defective 1 (App-1)
- Presenilin enhancer 2 (Pen-2)
Amyloid B protein
- Extracellular
- produced mainly in neurons
- aggregates to amyloid
- different AB isoforms:
- C-terminal: -40 -42 (-39 -38 -43)
- N-terminal: 1- 2- 3- 5- ...
- important isoforms:
- AB-140 and AB-42
- AB1-42 aggregates faster than AB1-40
Alzheimer's disease genetics: Which mutations can cause early onset familial Alzheimer's disease?
- Mutations in the following genes may cause (early-onset) familial Alzheimer's disease:
- Amyloid precursor protein (APP)
- Presenilin-1 (PS-1)
- Presenlin-2 (PS-2)
- Familial (hereditary) cases: <0.1%
- Polymorphisms in several genes affect the susceptibility for late-onset Alzheimer's disease
On which chromosome is the APP encoded and can by mutation thus cause Early-onset AD (<65 years) ?
In Down syndrome trisomy of chromosome 21
(so they have relatively more chance of getting AD)
What mutations cause an increase in AB or AB42 production and thus cause FAD (familial AD)?
What do mutations within AB sequence effect and cause?
Presenilin mutations and AD
- Presenilin protein is part of the y-secretase complex
- majority of mutations are in presenilin-1
Do mutations with presenilin-1 / -2 increase or decrease the ratio AB42/AB40 and total amount of AB ?
Which polymorphisms in several genes affect the susceptibility for late-onset Alzheimer's disease?
- A polymorphism in APP (A673T) may be protective
- Polymorphisms in the Apolipoprotein E gene increase the susceptibility for AD
- Novel polymorphisms in CLU (clustering, ApoJ), PICALM (phosphatidylinositol binding Cathrin assembly protein), CR1 (complement receptor 1) affect AD
Why may a polymorphism in APP be protective?
- A coding mutation (A673T) in the APP gene that protects against AD and cognitive decline in the elderly without AD.
- Adjacent to the aspartyl protease B-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro
What is the APP mutation A673T?
- Alanine -> Threonine
- whole genome sequencing in 1795 Icelanders
- 40% reduction in amyloidgenic peptides
Why is the ApoE a risk factor for AD?
- lipid-binding protein
- important for lipid transport
- mediates interaction between lipids (VLDL, HDL) with receptors (LDL-receptor-related protein = LRP)
- synthesis
- liver
- brain
- 3 alleles: e2, e3, e4
- ApoE e4 allele is increased in AD and decreases the age-of-onset of AD
What is the effect of ApoE on AB?
- Affects aggregation of AB (and tau?)
- ApoE e4 leads to the formation of more plaques
On which chromosome is the Tau gene?
- Tau gene -> chromosome 17
- alternative splicing lead to tau isoforms with either e- or 4-repeats of 'microtubule-binding domains'
To what (other diseases) do mutations in Tau lead?
- alzheimer: 3- and 4- repeat tau: 1:1
- Aggregates of tau also in other "tauopathies:
- Pick's disease
- progressive supranuclear palsy
- corticobasal degeneration
- frontotemporal dementia-parkinsonism linked to chromosome 17 (FTDP-17)
- mutations in tau can lead to frontotemporal dementia with Parkinsonism (FTDP-17)
Amyloid beta production
- Produced by neurons
- released into the extracellular space
- production ratio: AB40:AB42 = 10:1
- after production AB is removed from the brain (=clearance)
What are the four pathways of normal AB clearance?
- Uptake and intracellular degradation
- Auto-antibodies (directed against AB)
- Proteolytic degradation of AB
- Clearance across the blood-brain barrier
Clearance AB:
Uptake and intracellular degradation & Auto-antibodies (against AB)
- Activation through different receptors
- Toll-like receptors
- (Auto)antibody (Fc) receptors
- uptake AB into microglia (phagocytosis)
How does proteolytic degradation of AB work?
- Neprilysin (NEP) -> decreases AB deposition
- Insulin-degrading enzyme (IDE)
- endothelin-converting enzyme (ECE-1, -2)
- angiotensin-converting enzyme (ACE)
- Plasmin
- Metalloproteases (MMP-2,-3,-0)
relaxed by microglia cells (and other cells)
What is and does the blood-brain barrier (BBB) do?
How does clearance of AB work across the BBB (Blood-brain barrier)?
- from brain to blood via:
- lipoprotein receptor-related protein (LRP-1)
- P-glycoprotein
- From blood to brain via:
- Receptor for advanced glycation end-products (RAGE)
- gp330 / megaliet
Binding of AB to LRP
Clearance of AB (by capillaries; LRP-mediated transport across BBB)
- Binding affinity LRP: mutated AB < AB42 < AB40
- Blocking LRP (RAP) inhibits AB binding
- AB clearance rate: mutated AB < AB42 < AB40
- Blocking LRP (aLRP, RAP) inhibits AB clearance
Does AB increase or reduce endothelial LRP expression?
What are other receptor-mediated transport in AB aggregation clearance?
- RAGE
- Mediates influx of AB from blood to brain
- down regulation of RAGE inhibits AB influx
- P-glycoprotein:
- may serve as an efflux pump for AB
- High cerebral AB levels correlated to low cerebrovascular P-gp levels
- Gp330/megalin
- may transport AB in complex with ApoJ into the brain
- Normally saturated with ApoJ: little effect on AB influx
What type of amyloid deposits are there?
- Diffuse plaque -> most frequent AB42
- classic plaque -> dense core minority AB42 and AB40
- cerebral amyloid -> antipathy (CAA) AB40
Aggregation assay Thioflavin T
- Only fluorescent when bound to B-sheets
- increase in fluorescence -> increase in fibril formation
How can the amyloid beta fibrils be seen?
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