Tong et al 2019 Ca2+ in AD

Question 1

What are the cytosolic, extracellular, and store [Ca2+] at physiological condition?
How are these maintained?

Answer 1

Cyt: 50-300nM -> due to PMCA and NCX
- Becomes uM range after Ca2+ release
Extracell: low mM range
Store: 1000x Cytosol -> due to SERCA

Question 2

What are 2 ways in which intracellular Ca2+ increases?

Answer 2

IP3R-mediated
- GqPCR activation (eg. noradrenaline) -> PLC activation -> IP3 production -> Ca2+ release
RyR-mediated (CICR)
- activate by increased cytosolic Ca2+
- also can form complexes with TRPV4 and BKCa for Ca2+ sparks

Question 3

How does a cell restore Ca2+ in stores?

Answer 3

Store-operated Ca2+ entry (SOCE)
- decreased Ca2+ is sensed by STIM proteins due to unbound
- STIM oligomerizes and translocate to plasma membrane junctions
- activate Ca2+ release activated channels (eg. Orai) -> Ca2+ influx into cytosol for SERCA uptake

Question 4

State the different types of VGCC and relevance to neurons

Answer 4

L-type: soma and dendrites
T-type: neuronal excitability
N, P/Q, R-types: dendritic Ca2+ for initiating synaptic transmission

Question 5

What are the major types of receptor operated channels? How are they activate? Provide examples of each.

Answer 5

ionotropic and metabotropic receptors
Both activated by ligand binding like glutamate, but ionotropic allows cationic influx of (Na, K, Ca) and metabotropic allows activation of PLC to increase store-release

ionotropic: AMPAR, NMDAR, purinergic receptors (respond to ATP)
metabotropic: mGluRs

Question 6

How do Abeta affect Ca2+ homeostasis?

Answer 6

Abeta:
- trigger Ca2+ release from IP3R and RyR
- block SERCA uptake and thus increase cytosol Ca2+
- leads to mitochondrial Ca2+ overload and increased ROS -> trigger mitochondrial permeability transition pore to extrude apoptotic signal (can be prevented by autophagy but in AD, this could be impaired too)

Question 7

How can familial AD mutations contribute to ER Ca2+ abnormality?

Answer 7

Mutant Presenilin:
- Can increase IP3R and RyR expression to allow exaggerated Ca2+ release (GOF) -> Sensitize the receptors via protein protein interaction
- Can lose ER leak channel function and thus increase driving force of Ca2+ release (LOF)

Question 8

What is the expression pattern of RyR in MCI and AD?

Answer 8

RyRs are increased in the cortex and HPC

Question 9

How can SOCE be affected in AD?

Answer 9

SOCE disruption is consistently observed in AD -> decreased ER Ca2+ store -> when this sustains, apoptosis can occur

Question 10

How is Ca2+ signaling related to lysosomal function?

Answer 10

Lysosomes have Ca2+ conc comparable to ER
They release Ca2+ for autophagic fusion events
vATPase important to acidify but also creates H+ gradient for Ca2+ exchange -> impaired in PSEN mutations

Question 11

How is ELN affected in AD?

Answer 11

• ELN is required for proper clearance of proteins like Abeta and pTau
• but autophagic vacuoles with undigested molecules are increased in AD
• vATPase impairment -> dysfunctional lysosome (due to alkalization and decreased Ca2+) -> can’t clear aggregated proteins because decreased degradation and autophagic fusion-> spread through cell death release or exocytosis

Question 12

How does mitochondria relate to Ca2+?

Answer 12

Ca2+ is shuffled between ER and mitochondria
Ca2+ entry is important for activation of dehydrogenase -> extrude H+ for electron transport chain and ATP production

Question 13

How is mitochondrial Ca2+ involved in AD?

Answer 13

excess ER Ca2+ release can cause excess mito Ca2+
excess Ca2+ can interfere with ATP production
Furthermore can facilitate formation of mitochondrial permeability transition pore (mPTP) -> release apoptotic factors
Excess mito Ca2+ -> oxidative stress -> promote tau hyperphospho

Mitophagy to counteract this is impaired in AD possibly caused by Tau