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The brain & neurodegeneration

34 important questions on The brain & neurodegeneration

What is a neurodegenerative disease?

A condition in which memory, behaviour and/or thinking are impaired.

What are 7 common neurodegenerative diseases?

- Alzheimer's
- Parkinson's
- Dementia with Lewy bodies (DLB)
- Frontotemporal lobar degeneration (FTLD)
- Amyotrophic lateral sclerosis (ALS)
- Expansion repeat diseases (Huntington's, SCA)
- Prion diseases

What are the pathological hallmarks of Alzheimer's disease?

- Neurofibrillary tangles (accumulation of (phosphorylated) tau)
- Neuritic plaques (accumulation of amyloid beta)

What is the typical structure of a neuritic plaque?

- Core: amyloid in a beta-sheet structure
- Around the core: more diffused amyloid-beta

What is typical about the amyloid plaques, when compared to other neurodegenerative diseases?

The amyloid plaques are always extracellular, so in the parenchymal tissue.

How is amyloid precursor protein changed into amyloid?

Normally amyloid precursor protein is cleaved by alpha-, beta-, and gamma-secretase, but in Alzheimer's the alpha-secretase is not active. Therefore, a hydrophobic larger part is released and forms Aβ-oligomers, and the Aβ-oligomers start to aggregate.

How do Aβ-oligomers and the Aβ-aggregates cause Alzheimer's?

They can directly damage neurons, and thereby induce cell death, but they also have kinase activity that can cause damage.

What is the difference betwen early-onset Alzheimer's and late-onset Alzheimer's?

Early-onset (5% of cases): an autosomal dominant mutation (so it is inherited)
Late-onset (95% of cases): genetic risk factors (no one-to-one inheritance)

So the neurofibrillary tangles are accumulation of phosphorylated tau. What is the normal function of tau?

- It is essential for the stabilization of microtubuli,
- and it is phosphorylated to allow the passing of motor proteins (after which it is dephosphorylated again),
- for which the kinase and phosphatase balance is very crucial.

What is wrong in Alzheimer's disease in the function of tau?

- There is a disbalance between the kinases and phosphatases,
- which causes increased activity in kinases,
- which causes build-up of phosphorylated tau.

How does phosphorylated tau form the neurofibrillary tangles?

Phosphorylated tau is very hydrophobic, so it starts clumping together, forming aggregates.

How does the accumulation of phosphorylated tau induce neurodegeneration?

The accumulation of tau inside a cell eventually causes the cell to die, causing neurodegeneration.

What do the microglia do in Alzheimer's disease?

- They accumulate in the neuritic plaques, attempting to phagocytose it,
- but the core is too dense to do so,
- and they start to secrete cytokines and ROS,
- thereby harming nearby neuronal cells.

How can the aggregation of amyloid and tau be visualised in living patients?

By adding a ligand that specifically binds to these aggregates, and then performing a PET scan.

When is the diagnosis of dementia given, and how does this relate to the pathology?

- At an MMSE (measure for cognitive ability) of 23 or lower,
- but the amount of plaques and neurofibrillary tangles is already very high before that point is reached.

There are a lot of types of frontotemporal lobar degeneration (FTLD), but what is the most important clinical syndrome?

Primary progressive aphasia (PPA)

What are two types of FTLDs in which tau accumulates?

- Picks disease (sporadic, so not genetic)
- FTLD-17 (mutation in tau-protein)

What disease do you get when you have a mutation in the enzymes that cleave amyloid precursor protein, and what disease do you get when you have a mutation in tau protein?

- Mutation in secretase enzyme: Alzheimer's
- Mutation in tau protein: FTLD (so not Alzheimer's)

What is the difference between the FTLD TDP-type disease and ALS?

In ALS the TDP-inclusions are in a different position in the brain, namely the motor neurons in the cortex, and the motor neurons in the spinal cord.

What shows the relatedness of FTLD-TDP and ALS?

That physicians nowadays often speak of a spectrum of FTLD-TDP and ALS (so people in a family could have the same mutation, but a different disease)

What is very recently discovered in FTLD-TDP and ALS?

- That nucleic acid repeat expansion plays an important role in these diseases,
- which is the repetition of GGCCCC,
- that causes abnormal proteins to be formed,
- resulting in build-up of abnormal proteins (neurotoxicity)

Which ORF repeat expansion is the one that plays an important role in FTLD-TDP and ALS?

Repeat expansion in the C9orf72.

Who likely spread the C9orf72 repeat expansion (which is very prominant in FTLD-TDP and ALS patients)?

The Vikings.

In which diseases do these repeats in ORFs also play a role?

- Huntington's disease
- Spinocerebellar ataxias

Give a summary of the aggregates and inclusions in Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and frontotemporal dementia.

- Alzheimer's: amyloid beta and tau
- Parkinson's: alpha-synuclein
- Creutzfeldt-Jakob: Prion protein
- Frontotemporal dementia: tau and TDP43

What is Huntington's disease, and what are the hallmarks?

- A movement disorder,
- with CAG repeats in the huntington gene.
- Image: the brain has selective degeneration of the striatum (caudate nucleus and putamen),
- and cells have inclusions in the nucleus.

What is Parkinson's disease, and what are the hallmarks?

- A movement disorder (unintended & uncontrollable movements),
- in which there is a loss of dopaminergic neurons in the midbrain.
- Hallmark: Lewy bodies: deposits of alpha-synuclein (image)

What is Creutzfeldt-Jakob disease (Prion disease)?

A rapidly progressing dementing illness (duration of disease: months), which is potentially infectious.

What is Creutzfeldt-Jakob disease characterized by?

By spongiform (many tiny holes start to form in the brain, looking like a sponge) transformation of the cerebral cortex and deep grey matter structures.

What is the spongiform transformation in Creutzfeldt-Jakob disease caused by?

By prions, which are misfolded proteins that have the ability to cause nearby proteins to also collaps in an abnormal 3D-structure (the way this disease spreads throughout the brain possibly infectious)

Apart from prion proteins, for which proteins is this mechanism of propagation also suggested?

- Amyloid beta
- Tau
- TDP43
- Alpha-synuclein

How can misfolded proteins be spreaded to other neurons?

Via the synapses

So in summary, what are most neurodegenerative diseases characterized by?

By accumulation of misfolded proteins:

tau: Alzheimer's / FTLD-tau
amyloid-beta: Alzheimer's
TDP43: FTLD-TDP / ALS
Alpha-synuclein: Parkinson's / dementia with Lewy bodies
Prion protein: Creutzfeldt-Jakob disease

How do the accumulations and misfolding of proteins lead to the neurodegenerative diseases that are discussed in this lecture?

- Misfolded proteins spread through the brain (neuron-to-neuron)
- Protein aggregates affect cellular functioning
- Microglia are activated (neuroinflammatory response)
- The Unfolded Protein Response (UPR) / Protein degredation pathways
- Neuronal function / Synaptic dysfunction

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

Pathology Part II

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