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

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Pathology of nerves system Alzheimer's disease

Q: 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

Q: Alzheimer's disease metabolism: which proteins are abnormally folded?

Tau proteins Amyloid beta protein

Q: How does Tau fosforylation work?

Tau is a protein that bind to microtubuli and stabilizes them Tau in Alzheimer brains is hyper-fosforylated

Q: Why do we see neurofibrillary tangles in AD?

Hyperphosphorylation by kinases dephospho rylation normally through phosphates in AD: decreased activity phosphatases

Q: Tau protein in Alzheimer's disease

Healthy area: microtubules organized Diseased area: microtubules collapse Essential metabolites cannot be transported Neuronal loss

Q: Amyloid Beta (AB) protein and Non-amyloidgenic pathway

Cleavage with B- and Y-secretase three cleavage products: sAPPB Amyloid B C99 B = Beta

Q: APP processin: B-secretase and a-secreatase

B-secretase enzymes: 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)

Q: APP processing: y-secretase

Protease complex presenilin (Psn) Nicastrin (Nct) Anterio pharynx defective 1 (App-1) Presenilin enhancer 2 (Pen-2)

35 important questions on Pathology of nerves system Alzheimer's disease

What is the most prevalent form of dementia?

Alzheimer's disease

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?

Tau proteins
Amyloid beta protein

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

B-secretase enzymes:

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

Protease complex

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) ?

Chromosome 21

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)?

Mutations on N- or C-terminal of Amyloid beta

What do mutations within AB sequence effect and cause?

Mutations within Amyloid beta sequence affect AB aggregation and cause vascular variants of AD

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 ?

Increase the ratio AB42/AB40 or 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?

Apolipoprotein E (ApoE):

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?

Mutations in tau lead to frontotemporal dementia, not AD

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)

Microglial cells

Activation through different receptors
Toll-like receptors
(Auto)antibody (Fc) receptors
uptake AB into microglia (phagocytosis)

How does proteolytic degradation of AB work?

AB-degrading enzymes

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?

Separates peripheral circulation from brain circulation.

How does clearance of AB work across the BBB (Blood-brain barrier)?

Receptor-mediated transport:

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?

AB reduces 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?

With atomic force miscopy (proto)fibrils can be visualised

The question on the page originate from the summary of the following study material:

Human Pathology

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