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Pathology dt2 > Chapter 23: Lecture Neurodegeneration > Flashcards

Chapter 23: Lecture Neurodegeneration Flashcards

1
Q

What are the learning objectives of this lecture?

you obv don’t have to learn this, it’s to show you what will be discussed

A

After this lecture you will:

  • be able to describe the basic cellular composition and structure of the brain
  • know the main pathological hallmarks of the most common neurodegenerative diseases
  • be able to describe common disease mechanisms in neurodegenerative diseases
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2
Q

What is the lecture overview?

you obv don’t have to learn this, it’s to show you what will be discussed

A
  1. Introduction: brain structure and cells
  2. Alzheimer’s disease
  3. Frontotemporal lobar degeneration and amyotrophic lateral sclerosis
  4. Parkinson’s disease
  5. Prion diseases, protein misfolding and neurodegeneration
  6. Take home messages
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3
Q

What are different cells that we recognize in the brain? (and their function)

A

Cells in the CNS
1. Neurons: main functional unit

  1. Glia:
    a) Astrocytes: maintain CNS homeostasis and orchestrate CNS repair
    b) Oligodendrocytes: synthesize myelin
    c) Ependymal cells: cover the ventrikles
    d) Microglia: brain macrophages

3) Other cell types: endothelium, fibroblasts, smooth muscle cells, pericytes etc.
All cell types work together to maintain CNS homeostasis and proper functioning

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4
Q

What is in the grey and white matter?

A

Grey: neurons (cells)
White: axons (myelin)

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5
Q

Which cells form the myelin sheaths?

A

Oligodendrocyte

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6
Q

What are the ‘macrophages’ of the brain?

A

Microglia

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7
Q

What are the functions of astrocytes?

A

They perform a variety of tasks, from axon guidance and synaptic support, to the control of the blood brain barrier and blood flow

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8
Q

There are more than 100 conditions that impair memory, behavior and thinking (dementia). What are a couple of them?

A
  • Alzheimer’s disease (AD)
  • Parkinson’s disease (PD)
  • Dementia with Lewy bodies (DLB)
  • Frontotemporal lobar degeneration (FTLD)
  • Amyotrophic lateral sclerosis
  • Expansion repeat diseases (Huntington, SCA)
  • Prion diseases
  • ……
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9
Q

Is there hypertrophy, hypotrophy or atrophy in advanced Alzheimer’s disease (AD)?

A

Atrophy (the brain is much smaller/less volume and ventricles are enlarged)

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10
Q

Which regions are primarily affected by AD?

A

Hippocampus and fronto-temporal cortex (but it will spread to all cortical areas)

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11
Q

What two pathological hallmarks will be recognized in AD?

A

Neuritic plaque and neurofibrillary tangle

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12
Q

What do the neuritic plaques contain?

A

Fibrillar amyloid-beta

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13
Q

How can amyloid-beta form?

A

An amyloid precursor protein (APP) can be cleaved in different ways (such as alpha, gamma and also beta). Beta is the ‘wrong’ cleaving where an insoluble/hydrophobic oligomer of Aß will be formed -> aggregates -> fibrils

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14
Q

True/false: AD occurs when there is an accumulation of Aß

A

True

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15
Q

Is AD associated with an immune response?

A

Yes! You will see many active microglia around a plaque (harming more than they heal unfortunately)

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16
Q

True/false: Aß cannot be used as a biomarker

A

False

17
Q

There is increased phosphorylation of … protein in Alzheimer’s disease

A

tau

18
Q

Does phosphorylated tau occur in the neuron or outside the neuron?

A

Outside the neuron

19
Q

Does Aß occur in the neuron or outside the neuron?

A

outside / between neurons

20
Q

Can plaques that are associated with AD also occur in healthy patients?

A

Yes

21
Q

What are three differences between Aß and Tau in AD?

A
  1. Aß is extracellular, Tau is intracellular
  2. Aß is incorrectly cleaved, Tau is incorrectly phosphorylated
  3. Aß starts accumulating in the cortex, Tau in the hippocampus
22
Q

What does the amyloid beta cascade hypothesis propose?

A

Increased Aß production (in genetic AD) -> decreased clearance of Aß (in sporadic AD) -> Aß oligomers -> Aß fibrils -> synaptic and neuritic injury -> inflammation/oxidative injury -> tau phosphorylation -> tangles -> neuronal dysfunction/loss -> dementia

23
Q

Do most people have sporadic of genetic AD?

A

Sporadic

24
Q

Which is ‘better’ associated with cognitive decline, accumulation of Aß or Tau?

A

Tau (like noted before, also healthy individuals can have high accumulation of Aß without symptoms)

25
Q

Which protein accumulates in Fronto-temporal dementia (FTD)?

A

Tau (but no Aß!)

26
Q

What other diseases also have an accumulation of tau? (besides AD and FTD)

A

Picks disease (but no Aß!)

27
Q

are protein aggregates always toxic?

A

No

28
Q

FTD is also associated with TDP-43 inclusions. What is this?

A

TAR DNA-binding protein 43 (TDP-43) is a highly conserved nuclear RNA/DNA-binding protein involved in the regulation of RNA processing. The accumulation of TDP-43 aggregates in the central nervous system is a common feature of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE)

29
Q

What part of the brain is damaged in Parkinson’s disease (PD)?

A

Substantia nigra

30
Q

What typical protein aggregation is seen in PD?

A

Lewy bodies of alpha-synuclein

31
Q

Which cells are lost in PD?

A

Dopaminergic neurons in substantia nigra (loss of mobility)

32
Q

What is seen histolically in Prion disease?

A

Spongiform encephalopathy and accumulation of prion protein

33
Q

What is the take home message of this lecture?

A

Most neurodegenerative disorders are characterized by accumulation of misfolded proteins
• Amyloid beta: Alzheimer’s disease
• Tau protein: Alzheimer ’s disease, FTLD-tau
• TDP-43: FTLD-TDP
• Alpha-synuclein: Parkinson’s disease
• Prion protein: Creutzfeldt–Jakob disease

Misfolded proteins are able to spread throughout the brain and transfer from cell-to-cell (neuron-to-neuron)

Protein aggregates affect cellular functioning
• Activation of microglia (neuroinflammatory response)
• Protein degradation pathways
• Neuronal function/synaptic dysfunction

Pathology dt2 (39 decks)

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