Progressive and fatal, neurodegenerative disease, most common cause of dementia, starts in the hippocampus and spreads outwards
What do you lose to Alzheimer's
Loss of neurons, memories, and cognitive function (irreversible)
Dendrites
Receives signals from surrounding neurons
Soma
Cell body with organelles
Axon
Long extension of the cell, carries neurotransmitters, nutrients and signals from the presynaptic neuron to the axon terminal. Has a myelin sheath
Synaptic cleft
Gap where the presynaptic neuron axon terminals meet postsynaptic neuron dendrites
Microtubules
Essential for nutrient transport and structural support. Stabilized by tau proteins
Cholinergic neurons release a neurotransmitter called
Acetylcholine = acetyl-CoA + choline
What is Choline acetyl transferase (CAT)
An enzyme that makes acetylcholine
What is acetylcholinesterase
An enzyme that breaks down acetylcholine.
In Alzheimer's patients(cholinergic neuron degeneration)
The pathway is downregulated (less CAT, less acetylcholine)
Acetylcholinesterase inhibitors
Inhibit the enzyme that breaks down acetylcholine so that it is degraded less frequently and is active longer
Amyloid precursor protein (APP)
Transmembrane protein that plays an important role in the function, maintenance, and repair of neurons
Normal B-Amyloid Plaque processes
More alpha secretase than beta secretase. Normal production and clearance of amyloid beta. Gamma secretase cuts to form a soluble peptide
B-Amyloid Plaque processes in Alzheimer's patients
More beta secretase than alpha secretase. Gamma secretase cuts to form a longer peptide. HIgher production of insoluble amyloid beta and lower clearance of amyloid beta both lead to plaques
How do amyloid beta plaques cause brain deterioration?
Excessive release of toxic cytokines → inflammatory response → neuron loss. Overactivation of microglial cells and astrocytes → build-up of glutamate → neuron damage. Crowd synaptic clefts → block receptors → decreased communication between neurons
NMDA Antagonists
Inhibit NMDA receptors on the postsynaptic neuron so that excess glutamate has no effect on neurons. Relieves symptoms, but does not cure disease
Neurofibrillary tangles (TAU)
Have microtubules (a key structure that allow molecules/ nutrients from the stroma to reach the axon), and TAU proteins (forms subunits in microtubules to hold them together)
In Alzheimer's patients there are
Hyperphosphorylated TAU (many phosphate groups attached to TAU, causing tangles). Microtubules falling apart and fibrillary tangles formed will both contribute to neuron death.
Down Syndrome
Extra APP (B-Amyloid Plaques) gene on extra chromosome 21
ApoE4
Less effective at removing amyloid aggregates
Intertumoral Heterogeneity (between individuals)
Genetic differences between different individuals with the same type of cancer, personalized medicine
Intratumoral Heterogeneity (within a single patient)
Genetic differences among cells of the same tumor within the same individual, precision medicine
Single cell genome sequencing
The genome of each individual cell within a tumour splice can be sequenced
Clonal Evolution
Mutations that encourage proliferation accumulate, eventually leading to uncontrollable cell growth
Clonal expansion and genetic heterogeneity create
Obstacles for treatment, drug resistance
Oncogenic cells will ...
Proliferate, avoid apoptosis, grow, move and invade, create new blood vessels (angiogenesis), evade body's immune response
Driver Mutations
Contribute to cancer development. Required for causation, progression and maintenance of cancer
Passenger Mutations
Do not contribute to cancer development. Normal mutation processes. No growth advantage (no selection)
Nature (2009): 2-5 driver mutations to
Classify as cancer
Driver mutations fall under two categories
Proto -oncogenes and tumour suppressor genes (both normally present in cells, driver mutations tend to be present because they are more likely to lead to cancer progression)
Proto -oncogenes
Mutations in genes are likely to lead to oncogenic phenotype
Tumour suppressor genes
Mutation prevents this gene from performing its normal job with suppressing tumorigenic cells (ex: affects cell cycle checkpoints)
p53
The most common driver mutation (over 60% of cancers involve this mutation), guardian of the genome
What is a transcription factor?
Proteins that help turn specific genes on or off by binding to nearby DNA
How are cancer stem cells different from normal stem cells?
Cancer stem cells divide slowly, but non-cancer stem cells divide rapidly (resistant to chemotherapy, results in tumor relapse as persistent cancer stem cell remains)
Cancer stem cell specific therapy
Targets the actual cancer stem cell that sustains the tumor, results in tumor regression → new direction of therapy