Signalopathies Flashcards
Alzheimer’s disease
Late onset occurs after 65 years. Most common
Early onset between 30 and 65 years. 5-10% of cases. Rapid progression
Early symptoms are mild memory loss, changes in behaviour
Progressive symptoms are loss of speech, movement and death
Neurofibrillary tangles
Inside neurons
Phosphorylation of tau protein by GSK-3
Aggregation of phosphorylated tau into tangles
Removal of tau protein interferes with neuronal transport
Amyloid plaques
Outside neurons
Cleavage of amyloid precursor protein (APP) to Beta-amyloid (A-beta) fibres
Polymerisation of Abeta fibres to beta-amyloid plaques
Abnormal amyloid levels result in neuronal cell death
Non-amyloidogenic pathway
APP synthesised in ER-golgi and transferred to plasma membrane
Cleaved by alpha-secretases to soluble APP-alpha and C-terminal fragment alpha (CTFa)
CTFa hydrolysed by Presenilin-1 (PS1), releasing APP intracellular domain AICD (TF)
APP recycled through endosomal pathway
No beta-amyloid released
Amyloidogenic pathway
Internalised APP cleaved by beta-secretases to C-terminal fragment Beta (CTFB)
CTFB hydrolysed by gamma-secretase complex (PS1/2), releasing B-amyloid and AICD
Aggregation of A-beta to form oligomers, fibrils and plaques
Interaction of oligomers with cellular prion protein resulting in apoptosis
AICD
TF AICD released by hydrolysis of CTFalpha and CTFbeta by PS1
Leads to remodelling of Ca2+ signalosome
N-terminal soluble APPB hydrolysed to N-terminal APP
N-APP activates caspase-3 (apoptosis) and caspase-6 (axon pruning)
Abeta oligomer-induced Ca2+ influx
Cellular prion protein acts as a receptor for Abeta (influx of calcium)
Abeta oligomer inserts into the membrane to form calcium permeable channels
Ca2+ entry enhanced through ROCs (NMDA receptor)
Remodelling of Ca2+ signalosome
AICD leads to increased SERCA pump expression (increased Ca2+ in ER/SR)
Increased RYR expression (increased release from ER/SR)
Decreased Calbindin Ca2+ buffer expression
Increased calcineurin expression
Affects signalling and homeostasis. Hypersensitive to stimuli
Ca2+ release from internal stores
B-amyloid oligomers increase IP3 production by interacting with GPCR calcium-sensitive receptor.
Presenilin 1 leak Ca2+ from ER, preventing build-up so normal release occurs following stimulus.
Mutations in PS1 (Alzheimer’s) prevent leakage so Ca2+ builds up and there is excessive release
Production of ROS also leads to activation of IP3R
Alzheimer’s Ca2+ dysregulation
Calcium-induced apoptosis
Calcium/ROS-induced astrocyte/neuronal cell death
Disruption of synaptic plasticity, learning and memory
Ca2+ and apoptosis
Increased cytosolic calcium causes release of mitochondrial cytochrome c (Cyt c)
Apoptosome formation, cleavage of proteins and DNA
Astrocyte-induced neuronal death
Astrocytes support neurons in the CNS
B-amyloid/Ca2+ induced activation of NADPH oxidase increases ROS
Depletion of glutathione (GSH) in astrocytes and neuronal cells
ROS-induced cell death
Disruption of synaptic plasticity, learning and memory
Synaptic efficiency modified due to changes in sensitivity of AMPAR glutamate receptor
Causes LTD or LTP
Ca2+ control of LTD/P
High cytosolic Ca2+ enhances sensitivity to glutamate leading to LTP and memory formation
Low Ca2+ reduces sensitivity leading to LTD and erasure of temporary memory
In AD, dysregulation means calcium is permanently elevated. LTP occurs but not consolidated (LTD immediately erases)
