Podcast
Questions and Answers
Which factor is commonly associated with protein aggregation in late-onset neurodegenerative diseases?
Which factor is commonly associated with protein aggregation in late-onset neurodegenerative diseases?
What is a notable characteristic of neurons as they age?
What is a notable characteristic of neurons as they age?
Which neurodegenerative disease is primarily associated with the loss of proteostasis?
Which neurodegenerative disease is primarily associated with the loss of proteostasis?
What aspect of the brain's functional abilities mimics a supercomputer?
What aspect of the brain's functional abilities mimics a supercomputer?
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What best describes synaptic plasticity in relation to neurons?
What best describes synaptic plasticity in relation to neurons?
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What is the primary association of Aβ peptide in the context of Alzheimer’s Disease?
What is the primary association of Aβ peptide in the context of Alzheimer’s Disease?
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Which cellular event is Tau protein primarily involved in within neurons?
Which cellular event is Tau protein primarily involved in within neurons?
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What does familial Alzheimer’s Disease typically indicate regarding its onset?
What does familial Alzheimer’s Disease typically indicate regarding its onset?
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How do specific mutations in the APP gene affect Alzheimer’s Disease risk?
How do specific mutations in the APP gene affect Alzheimer’s Disease risk?
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What implication does the presence of both causative and protective APP alleles have for Alzheimer’s Disease?
What implication does the presence of both causative and protective APP alleles have for Alzheimer’s Disease?
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Which of the following accurately describes the role of neurofibrillary tangles in Alzheimer’s Disease?
Which of the following accurately describes the role of neurofibrillary tangles in Alzheimer’s Disease?
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What is a significant characteristic of microtubules in relation to neuronal function?
What is a significant characteristic of microtubules in relation to neuronal function?
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Which factor is implicated in the development of synaptic plasticity?
Which factor is implicated in the development of synaptic plasticity?
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What is the lifespan of neurons compared to other cell types mentioned?
What is the lifespan of neurons compared to other cell types mentioned?
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Why are neurons particularly vulnerable despite their long lifespan?
Why are neurons particularly vulnerable despite their long lifespan?
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What characterizes the aging process of neurons?
What characterizes the aging process of neurons?
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What is the fundamental aspect of neurons that allows them to adapt to stimuli?
What is the fundamental aspect of neurons that allows them to adapt to stimuli?
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Which genetic factor has the largest influence on late-onset Alzheimer's Disease (LOAD)?
Which genetic factor has the largest influence on late-onset Alzheimer's Disease (LOAD)?
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Which statement correctly distinguishes dementia from normal aging?
Which statement correctly distinguishes dementia from normal aging?
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What is a primary biological mechanism linked to neuron loss in aging?
What is a primary biological mechanism linked to neuron loss in aging?
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How do genetic studies contribute to understanding Alzheimer's Disease?
How do genetic studies contribute to understanding Alzheimer's Disease?
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Study Notes
Molecular Basis of Aging: Loss of Proteostasis & Neurodegeneration
- Loss of proteostasis is a key hallmark of aging
- Protein aggregation is a key feature in neurodegenerative diseases
- Dementia is a disease, not a part of normal aging
Aims of this Lecture
- Understand the key components regulating proteostasis
- Appreciate the role of protein aggregation in aging and late-onset neurodegenerative diseases
- Understand the genetics of Alzheimer's Disease (AD)
- Describe the molecular basis for neurodegeneration in early-onset familial AD
Proteostasis in Aging
- Young adult worms maintain a balanced proteome by efficiently clearing misfolded proteins
- Ageing is associated with proteome imbalance
- Inefficient clearance of misfolded proteins
- Loss of chaperones (e.g., sHSP)
- Increase in the number of toxic misfolded protein oligomers
- Insoluble inclusions: large aggregates of misfolded proteins
Proteins Can Be Damaged
- Just like DNA, proteins can also be damaged
- Aging is characterized by:
- Increased damage
- Failure of removal mechanisms
- A vicious cycle that perpetuates the ageing process
A Balancing Act
- Protein Production vs. Removal
- Reduced protein clearance (proteosome, autophagy) combined with increased production and aggregation of protein leads to impairment
Protein Aggregation and Neurodegeneration
- Protein aggregation is common in late-onset neurodegenerative diseases, like Alzheimer's and Parkinson's Disease
- Alzheimer's Disease: features include amyloid β peptide, phosphorylated tau, amyloid plaques, neurofibrillary tangles
- Parkinson's Disease: features include α-synuclein and Lewy bodies
Human Brain Complexity
- The human brain is a sophisticated biological instrument with high energy usage (>1016 complex operations per second)
- High energy consumption is supported by brain metabolism
- Advanced computing parallels like the K supercomputer are informed by biology
Neurons: Brain's Cellular Processors
- The human brain contains approximately 37 trillion cells, including 100 billion neurons and 100 trillion connections (synapses) with each neuron having ~1000 synapses
- Neurons are specialized for storing & retrieving biological information.
- Neurons are terminally differentiated and non-proliferative
Cell Proliferative Rates
- Cells proliferate at different rates
- Mitosis cells divide continuously (e.g., skin cells)
- Quiescent/post-mitotic cells divide less frequently or not at all, depending on stimulation (e.g., liver cells)
- Fixed post-mitotic cells never divide (e.g., neurons)
- Telomere length varies between different cell types
With Great Power, Comes Great Susceptibility
- The lifespan of neurons is a double-edged sword, meaning essential to function but also increases its vulnerability
- Neurons repair themselves rather than regenerate, making them susceptible to long term accumulation of damage
- Neurons continuously adjust synaptic connections based on stimulation
Alzheimer's Disease
- Dementia is a disease of aging, not a normal part of the aging process
- Understanding the relationship between aging, loss of proteostasis, and neuron loss will help treat the disease (first clues found in genetics)
The Genetic Landscape of AD
- Genetic causes of AD include familial (early-onset) and sporadic (late-onset) forms
- Genetic risks include amyloid-beta precursor protein (APP), presenilin 1 (PSEN1), and apolipoprotein E4 (APOE4) mutations
Amyloid-β Precursor Protein (APP)
- APP is a transmembrane protein involved in neuronal stem cell development, intracellular signaling, axonal/dendritic process growth, synaptic plasticity, lipid homeostasis
- This protein is implicated in regulating lipid homeostasis & synthesis of specific lipids
Familial Alzheimer's Disease
- Early-onset AD is caused by genetic mutations
- Associated with amyloid precursor protein (APP) and presenilin (PSEN) genes
- Autosomal dominant mutations
APP Proteolytic Processing
- APP is cleaved by secretases to either a non-amyloidogenic product or an amyloidogenic product
- Amyloidogenic products can lead to aggregation and contribute to AD pathology
- Secretases specifically cut APP at target sites, producing variable sizes of Aβ peptides; the variable lengths of Αβ peptides is important for understanding and preventing AD
Gamma-Secretase
- Gamma-secretase is a protein complex involved in APP processing and Aβ production
- Cleavage substrates within membranes (e.g., APP, Notch)
Aβ Production by γ-Secretase
- Secratases cut at specific target sites but vary.
- y-secretase variable cleavage generates different sizes of Aβ peptides; it nibbles off the ends of the peptide after cleavage
- Different lengths of Aβ peptides have different toxicities
Many Mutations in APP
- Some Mutations in APP increase the production of Aβ1-42
- Mutations close to the γ-secretase cleavage site can increase amyloidogenic processing of APP leading to increased neurotoxicity and AD
- Other mutations (e.g. A673T in APP) can be protective by decreasing cleavage or increasing α-secretase cleavage to limit Aβ production
APPs on Chromosome 21
- Down Syndrome (Trisomy 21) is a progeroid syndrome with three copies of APP
- Persons with Down Syndrome have more amyloid plaques and Tau tangles in the brain, which often leads to AD pathology by age 40
AD Has Two Major Pathological Hallmarks
- Extracellular amyloid plaques (Aβ)
- Intracellular neurofibrillary tangles (tau)
- Mutations in the tau gene (MAPT) in some dementias, but not familial AD
Microtubule Associated Protein Tau (MAPT)
- Tau proteins are essential for transporting proteins, vesicles, and organelles throughout axons/synapses
- Tau stabilises microtubules; important for synaptogenesis; dysfunction leading to aggregation of tau (neurofibrillary tangles)
- Aggregated Tau (NFTs) causes cognitive decline & dysfunction
Does Aβ Amyloid or Tau Fibrils cause AD?
- Both Aβ and tau are associated with AD, but which is the primary cause?
- Specific mutations in PSEN and APP definitively cause the disease (100% penetrance)
- Rare mutations in APP protect against AD, suggesting Aβ is the primary driver.
New Therapeutic Strategies for AD
- Current strategies focus on clearing toxic Aβ species and Tau pathology
- Drugs targeting BACE1, y-secretase, Aβ antibodies, and Tau based drugs have been tested, but with limited success so far
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Description
Explore the critical concepts related to the loss of proteostasis and its impact on neurodegenerative diseases, particularly focusing on Alzheimer's Disease. This quiz will enhance your understanding of how protein aggregation contributes to aging and the mechanisms behind these processes.
