Alzheimer's Disease Flashcards
AD is the most common cause of ___?
Dementia
What are 2 molecular characterizations of AD?
- Amyloid-beta plaques
- Neurofibrillary tangles (NFTs)
Describe amyloid-beta plaques.
Clumps of AB peptides (toxic fragments derived from the Amyloid Precursor Protein [APP])
Describe neurofibrillary tangles (NFTs).
- Clusters of hyperphosphorylated (excessive phosphorylation or lots of phosphate groups) tau proteins
What is the function of tau proteins?
Stabilize the cell’s transport structures (microtubules)
What is a peptide?
- A short chain of amino acids
- Can act as signaling molecules, hormones, or byproducts of protein processing
What is APP and its relation to AD?
- Amyloid Precursor Protein
- Transmembrane protein mostly found in neurons
- Helps out with cell growth and synaptic health
Explain the normal processing pathway of APP.
Non-amyloidogenic pathway
- alpha-secretase cleaves APP and splits it in 2
- This prevents the formation of AB peptides and produces soluble APP-alpha
- No harmful peptides are formed
What does it mean when a protein is cleaved?
An enzyme cuts a protein or peptide at a specific site to turn the protein on or off or produce fragments with different functions
Explain the abnormal processing pathway of APP.
Amyloidogenic pathway
- beta-secretase cleaves APP at a different site
- C99 is produced (new fragment)
- gamma-secretase cleaves C99 to release AB peptides into the extracellular space
- AB peptides (think of AB42) aggregate into plaques
What do AB plaques look like?
- Dense, spherical deposits in the brain tissue
- Central core of aggregated AB, surrounded by a halo of damaged neurons and glial cells (astrocytes and microglia)
Define 3 causes of AD formation.
- APP metabolism shifts
- Tau protein dysfunction
- Age-related factors
An increased activity of ____ and ____ in neurons would lead to excessive AB production.
beta-secretase, gamma-secretase
How does AB accumulations affect tau proteins?
- Triggers tau hyperphosphorylation
- Tau loses ability to stabilize microtubules and form tangles inside neurons
How does age affect AB clearance?
- The older we get, the harder it is for our brains to clear AB peptides
- Inflammation and oxidative stress increases (more protein aggregation)
Describe the early stages of AD.
- AB peptides begin to cluster, forming oligomers (toxic to synapses)
- May occur years before symptoms appear
Describe the intermediate stages of AD.
- Larger AB plaques form
- Immune cells (microglia) are activated and release inflammatory molecules that damage neurons
- Tau tangles spread through the brain (inhibits intracellular transport and cause more neuronal loss)
Describe the late stages of AD.
- Widespread neuronal death
- Brain shrinkage
- Severe memory loss, disorientation, and motor impairment
List cognitive symptoms of AD.
- Progressive memory loss
- Difficulty solving problems
- Confusion
List behavioral symptoms of AD.
- Mood swings
- Depression
- Aggression
List physical symptoms of AD.
- Loss of coordination
- Incontinence
- Difficult swallowing
Describe current treatment for AD.
- Cholinesterase inhibitors
- Boost ACh (a NT involved with learning and memory) - NMDA receptor antagonists
- Reduce damage caused by excessive glutamate (a NT)
Describe experimental therapies for AD.
- Drugs targeting AB plaques
- Aim to reduce AB production or enhance its clearance - Drugs targeting tau tangles
- Focus on blocking tau aggregation or reducing its phosphorylation
What are some lifestyle interventions that could promote brain health and reduce AB accumulation?
Physical exercise and mental stimulation
