Biology 1002- Cycle 9

alzeimer’s disease

• progressive and fatal

• neurodegerative disease

what is the most common cause of dementia

Alzeimer’s disease

Where does Alzeimer’s start

hippocampus and spreads outwards

dendrites

receive signals from surrounding neurons

soma

cell body w/ organelles, responsible for keeping the cell alive

axon

long extension of the cell, ends in synaptic terminal, sends out electrical signals

synaptic cleft

gap where presynaptic neuron axon terminals meet postsynaptic neuron dendrites

cholinergic neurons release a neurotransmitter called

acetylcholine

choline acetyl transferase (CAT)

an enzyme that makes acetylcholine

acetylcholinesterase

an enzyme that breaks down acetylcholine

Binding of acetylcholine to the postsynaptic receptor is important for initiating a signal _____ so we can remember things

cascade

In AD patients - cholinergic neuron degeneration

this pathway (binding of acetylcholine to postsynaptic receptor) is dysregulated (less CAT, less acetylcholine)

What would be a good drug target to treat AD

acetylcholinesterase

Acetylcholinesterase inhibitors

inhibit the enzyme that breaks down acetylcholine

ex) rivastigmine

Rivastigmine (acetylcholinesterase inhibitor)

• inhibits acetylcholinesterase so that acetylcholine is degraded less frequently

• acetylcholine is active longer

Amyloid precursor protein (APP)

transmembrane protein that plays an important role in the function, maintenance, and repair of neurons

normal process for APP

• more alpha secretase than beta secretase

• normal production and clearance of amyloid beta

• gamma secretase cuts to form a soluble peptide

APP in AD patients

• more beta secretase than alpha secretase

• increased in insoluble proteins released from when y-secretase (gamma) cuts

Mutations in Presenilin-1 and 2 can cause y-secretase to prefer cutting…

42aa amyloid- beta proteins

Secretase must be cleared by

microglia, astocytes, and apolipoprotein E

• Higher production of insoluble amyloid beta

• Lower clearance of amyloid beta

leads to plaques

Amyloid beta plaques - normal function

• microglia sense amyloid-beta proteins

• release cytokines

• astrocytes activate and produce ApoE

• ApoE coats aggregates

• microglia engulfs them

How do amyloid beta plaques result in neuron death

• excessive glutamate byproduct from astrocytes released into synaptic cleft

• too many excitatory signals in synapse

• overstimulation of neuron

• neuron death

NMDA antagonists

• inhibit NMDA receptors on the postsynaptic neuron so that excess glutamate cannot bind and activate receptor

• relieves symptoms, does not cure the disease

microtubules

key structures of cells (allow molecules/nutrients from soma to reach axon)

TAU

type of protein that forms subunits in microtubules to hold them together

In AD patients (TAU)

there are hyperphosphorylated TAU (many phosphate groups attached to TAU causing tangles)

microtubules falling apart and fibrillary tangles formed both contribute to

neuron death

Genetic risks AD- down syndrome

extra APP gene on extra chromosome 21

genetic risks AD- presenilin 1 and 2

• autosomal dominant interitance

• catalytic region of gamma secretase favours large 42aa peptide formation

genetic risks AD- ApoE4

less effective at removing amyloid aggregates

What do we use to select for cells that die to try and cure the cancer

therapeutic selective pressure

intertumoral heterogeneity

• genetic differences between different individuals with the same type of cancer

• personalized medicine

• between individuals

intratumoral heterogeneity

• genetic differences among cells of the same tumor within the same individual

• precision medicine

• within a single patient

clonal expansion and genetic heterogeneity creates obstacles for treatment=

drug resistance

relapse occurs when…

a clone resists treatment (often chemotherapy) and continues proliferating

mutations that encourage proliferation accumulate, eventually leading

to uncontrollable cell growth

Oncogenic cells will…

Proliferate

Anti-apoptosis

Grow

Evade body’s immune response

Motility

Invasive

Angiogenesis

Driver mutations

• contribute to cancer development

• growth advantage (selected for)

• required for causation, progression, and maintenance of cancer

How many driver mutations to classify as cancer?

2-5 (depends on aggression of mutation)

passenger mutations

• do not contribute to cancer development

• “along for the ride”

• normal mutation processes

• no growth advantage (no selection), inert

endogenous sources

inside the body

• mutations, ROS

environmental

outside the body

• lifestyle factors, UV radiation

Is pathway active without typical presence of growth factor in cancer?

yes

Proto-oncogenes - gain of function

pathway is overexpressed

• cancer cells can induce receptor to be active

Oncogenic cells divide…

uncontrollably and without regulation

In cancer, what happens to mutant p53

can no longer bind DNA, preventing the transcription of p53 genes that act as the “stop signal” for cell division

tumour- supressor ex) p53 in cancer

• loss of function- loss of regulation of cell cycle

• p53 “guardian of genome” role in cell cycle arrest, apoptosis

• most mutations in DNA binding region of p53

Cancer stem cells divide

slowly, making them resistant to chemotherapy

Cancer stem cells are speculated to be the cell where

all the driver mutations accumulate

Cancer stem cell specific therapy

targets the cancer stem cell that sustains tumor, preventing relapse