Chapter 23: Lecture Neurodegeneration Flashcards
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
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
What is the lecture overview?
you obv don’t have to learn this, it’s to show you what will be discussed
- Introduction: brain structure and cells
- Alzheimer’s disease
- Frontotemporal lobar degeneration and amyotrophic lateral sclerosis
- Parkinson’s disease
- Prion diseases, protein misfolding and neurodegeneration
- Take home messages
What are different cells that we recognize in the brain? (and their function)
Cells in the CNS
1. Neurons: main functional unit
- 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
What is in the grey and white matter?
Grey: neurons (cells)
White: axons (myelin)
Which cells form the myelin sheaths?
Oligodendrocyte
What are the ‘macrophages’ of the brain?
Microglia
What are the functions of astrocytes?
They perform a variety of tasks, from axon guidance and synaptic support, to the control of the blood brain barrier and blood flow
There are more than 100 conditions that impair memory, behavior and thinking (dementia). What are a couple of them?
- 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
- ……
Is there hypertrophy, hypotrophy or atrophy in advanced Alzheimer’s disease (AD)?
Atrophy (the brain is much smaller/less volume and ventricles are enlarged)
Which regions are primarily affected by AD?
Hippocampus and fronto-temporal cortex (but it will spread to all cortical areas)
What two pathological hallmarks will be recognized in AD?
Neuritic plaque and neurofibrillary tangle
What do the neuritic plaques contain?
Fibrillar amyloid-beta
How can amyloid-beta form?
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
True/false: AD occurs when there is an accumulation of Aß
True
Is AD associated with an immune response?
Yes! You will see many active microglia around a plaque (harming more than they heal unfortunately)
True/false: Aß cannot be used as a biomarker
False
There is increased phosphorylation of … protein in Alzheimer’s disease
tau
Does phosphorylated tau occur in the neuron or outside the neuron?
Outside the neuron
Does Aß occur in the neuron or outside the neuron?
outside / between neurons
Can plaques that are associated with AD also occur in healthy patients?
Yes
What are three differences between Aß and Tau in AD?
- Aß is extracellular, Tau is intracellular
- Aß is incorrectly cleaved, Tau is incorrectly phosphorylated
- Aß starts accumulating in the cortex, Tau in the hippocampus
What does the amyloid beta cascade hypothesis propose?
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
Do most people have sporadic of genetic AD?
Sporadic
Which is ‘better’ associated with cognitive decline, accumulation of Aß or Tau?
Tau (like noted before, also healthy individuals can have high accumulation of Aß without symptoms)
Which protein accumulates in Fronto-temporal dementia (FTD)?
Tau (but no Aß!)
What other diseases also have an accumulation of tau? (besides AD and FTD)
Picks disease (but no Aß!)
are protein aggregates always toxic?
No
FTD is also associated with TDP-43 inclusions. What is this?
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)
What part of the brain is damaged in Parkinson’s disease (PD)?
Substantia nigra
What typical protein aggregation is seen in PD?
Lewy bodies of alpha-synuclein
Which cells are lost in PD?
Dopaminergic neurons in substantia nigra (loss of mobility)
What is seen histolically in Prion disease?
Spongiform encephalopathy and accumulation of prion protein
What is the take home message of this lecture?
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
