Signalopathies - Alzheimer's Disease Flashcards
What are some signalopathies?
Alzheimer’s disease (AD)
Pancreatitis
Polycystic Kidney Disease (PKD)
Huntington’s disease (HD)
EXTRA READING
= Diabetes = dysregulation of pathways regulating insulin secretion / sensitivity / insulin receptor
= Parkinson’s = related to AD, MAPK/ERK + JAK/STAT pathways can contribute to neuronal death and dysfunction
= Hypertension / Atherosclerosis = signalling pathways that regulate vascular tone, inflammation and angiogenesis = such as endothelin / nitric oxide signalling pathway
= Rheumatoid arthritis / MS = dysregulated immune responses = JAK/STAT pathway
What are some examples of Neurodegenerative disease (whose proteins affect Ca2+)?
Prion diseases
Huntington’s Disease
Alzheimer’s Disease
What is Alzheimer’s Disease?
Late-onset AD
= >65 years old
(senile dementia Alzheimer’s type, SDAT)
= most common form
Early-onset AD
= ages 30-65 years
= rare
= often progresses more rapidly than late-onset AD
Degeneration of healthy brain tissue (10-20 yrs for symptoms to appear)
Early symptoms
= mild memory loss
= changes in personality and behaviour
= decline in thinking abilities (cognition)
Progressive symptoms
= loss of speech and movement
= total incapacitation
= eventually death
Familial AD (FAD)
= follows certain inheritance pattern
Sporadic AD
= does NOT show an inheritance pattern
What are the hallmarks of AD?
Neurofibrillary tangles (inside neurons)
= 1. Phosphorylation of tau protein by glycogen synthase kinase-3 (GSK-3)
= 2. Aggregation of phosphorylated tau protein into tangles
= 3. Removal of tau protein interferes with neuronal transport
Amyloid plaques (outside neurons)
= 1. Cleavage of amyloid precursor protein (APP) to β-amyloid (Aβ) fibres
= 2. Polymerisation of Aβ fibres to β-amyloid plaques
= 3. Abnormal amyloid levels bring about neuronal cell death
Results in:
= nerve cells die
= brain shrinks
= ability to function deteriorates
How is Ca2+ signalling remodelling involved in Alzheimers disease? How does dysregulation occur?
Healthy neurons
= Ca2+ signalling has essential role in regulating synaptic plasticity, learning and memory
AD
= dysregulation of Ca2+ signalling pathways leads to neuronal dysfunction and cell death
(can be after ageing = sporadic) or after amyloid pathway mutations = familial)
= can be through dysregulation of intracellular Ca2+ homeostasis
(tightly regulated by pumps, transporters and channels)
= can be through activation of downstream signalling pathways
(chronic activation leads to neurotoxicity and synaptic dusfunction)
(EXTRA READING)
What is the amyloid cascade hypothesis in Alzheimer’s disease?
Non-amyloidogenic pathways:
- β-amyloid precursor protein (APP) synthesised in ER-Golgi transferred to the plasma membrane
2a. APP cleaved by α-secretases soluble APPα (sAPPα) and the C-terminal fragment α (CTFα) in the membrane
2b. CTFα is hydrolysed by presenilin-1 (PS1)
(part of γ-secretase complex)
= releasing the APP intracellular domain (AICD) - a transcription factor
= APP recycled through endosomal pathway
= NO β-amyloid release
Amyloidogenic pathways:
- Internalised APP is cleaved by β-secretases (BACE) = producing the C-terminal fragment β (CTFβ)
- CTFβ is hydrolysed by γ-secretase complex (containing PS1 or PS2) releasing β-amyloid and AICD
- Aggregation of β-amyloid monomers to form Aβ oligomers, fibrils and plaques
- Interaction of Aβ oligomers with cellular prion protein (PrPC) = apoptosis
- N-terminal sAPPβ is hydrolysed to N-terminal APP
- N-APP activates caspases-3 (apoptosis) and caspase-6 (axon pruning)
= loss of neuronal desity
What is the calcium hypothesis of Alzheimer’s Disease?
= Ca2+ signals responsible for controlling pre- and post-synaptic events
(dependent on number of neuronal Ca2+ entry and release channels)
AD results in Ca2+ dysregulation via:
= Ca2+ influx
= increased Ca2+ release from internal stores
What is Aβ oligomer-induced Ca2+ influx (as part of the calcium hypothesis in AD)?
Aβ oligomer-induced Ca2+ influx
= cellular prion protein (PrPc) - β-amyloid receptor
= Aβ oligomer insert into membrane to form channels
= enhance Ca2+ entry through ROCs: NMDA receptor
What is AICD (as part of the calcium hypothesis in AD)?
AICD
= transcription factor that is released by hydrolysis of CTFα and CTFβ by PS1
= remodelling of the Ca2+ signalsome
= increases SERCA pump expression (increases Ca2+ conc in ER/SR)
= increases RYR expression (increases Ca2+ release from ER/SR)
= decreases Calbindin Ca2+ buffer expression (decreases buffering of Ca2+ conc changes = decreases ability to restrict amplitude of Ca2+ signals)
= increases calcineurin expression
Reduced buffering of cytosolic Ca2+
= AICD = decreases calbindin expression = decreased buffering of Ca2+ conc changes
= neuronal calbindin D-28k decrease with age
= decreased ability to restrict amplitude of Ca2+ signals
How is Ca2+ released from internal stores (as part of the calcium hypothesis in AD)?
Aβ oligomer activation of calcium-sensitive receptor
= increases IP3
Presenilin 1 (PS1)
= catalytic core of γ-secretase
(acts as Ca2+ channel in ER)
Increased ROS
= IP3R agonist
Presenilins ‘leak’ Ca2+ from ER
= low Ca2+ conc in ER
= Ca2+ influx into hippocampal dendrite spine cytosol via SOCs (TRCO6/Orai2)
Mutations in PS1 can cause early-onset familial AD:
= increased ER Ca2+ conc
= reduced Ca2+ influx into hippocampal spines via SOCs
= enhanced IP3R/RYR mediated Ca2+ release due to Aβ
What are the consequences of Ca2+ dysregulation in AD?
- Ca2+ induced apoptosis
= increase in cytoplasmic calcium
= release of mitochondrial cytochrome c (Cyt c)
= apoptosome formation, caspase activation, cleavage of proteins (caspases) and DNA (nucleases) - Ca2+/ROS-associated astrocyte/neuronal cell death
= critical role of astrocytes in supporting neurons in CNS affected
= β-amyloid/Ca2+ induced activation of NADPH oxidase = increased ROS
= depletion of astrocyte / neuronal GSH
= ROS-induced cell death - Disruption synaptic plasticity, learning and memory
= synapse undergo modifications of synaptic efficiency
= Ca2+ induced changes in sensitivity of the AMPA receptor to glutamate in dendritic spines
= long-term potentiation (LTP)
= long-term depression (LTD)
= high Ca2+ conc = enhances sensitivity to glutamate = LTP = memory formation
= low Ca2+ conc = reduces sensitivity to glutamate = LTD = erasure of temporary memory
= increased Ca2+ release due to amyloid metabolism = increased resting Ca2+ conc = LTD = failure to form permanent memories
