Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

Table 1

Molecular mechanisms and players involved in AD and the expression of homeostatic synaptic plasticity.

	Roles in synaptic scaling	Involvement in AD	References
AMPAR scaffolding proteins
GRIP1	Synaptic accumulation and removal of GRIP1 mediate synaptic scaling and downscaling, respectively, by regulating synaptic AMPAR targeting.		[76, 77]
PICK1	PICK1 degradation mediates synaptic scaling.	PICK1 interaction with GluA2 mediates A-induced synaptic depression.	[78, 79]
Regulators of AMPAR trafficking
Arc/Arg3.1	Downregulation of Arc/Arg3.1 mediates synaptic scaling by increasing surface AMPAR density. Upregulation of Arc/Arg3.1 mediates synaptic downscaling by promoting AMPAR endocytosis.	Arc/Arg3.1 expression is elevated in AD and mediates activity-dependent generation of A by binding to presinilin-1 and regulating γ-secretase trafficking.	[80–82]
Homer1a	Downregulation of Homer1a mediates synaptic scaling, whereas upregulation of Homer1a mediates synaptic downscaling by regulating surface AMPAR density and Tyr-phosphorylation.		[83]
Regulators of synaptic AMPAR density
PSD-95	Synaptic accumulation of PSD-95 mediates synaptic scaling, whereas its interaction with TARP mediates synaptic downscaling.	Pathological level of A leads to PSD-95 degradation.	[84–89]
PSD-93	PSD-93 mediates synapticscaling.		[84]
GKAP	Synaptic accumulation and removal of GKAP mediate synaptic scaling and downscaling, respectively, by regulating surface AMPAR density.	Pathological level of A leads to GKAP degradation.	[90, 91]
Posttranslation modification of AMPAR
Calcineurin	Reduced calcineurin activity mediates synaptic scaling via GluA1-Ser845 dephosphorylation and subsequent synaptic trafficking of Ca^2+-permeable AMPARs.	In AD mouse model, increased activity of calcineurin induces dephosphorylation and synaptic removal of the GluR1 subunit of AMPAR.	[92, 93]
STEP61	Downregulation of STEP61 mediates synaptic scaling, whereas enhanced STEP61 upon chronic activity induces dephosphorylation of GluN2B and GluA2.	STEP61 expression is elevated in AD and mediates A-induced dephosphorylation and internalization of NMDARs and AMPARs, whereas inhibition of STEP61 prevents cognitive deficits and impaired hippocampal LTP in AD mouse models.	[94–98]
PP1	Downregulation of PP1 inhibitor-2 (I-2) mediates synaptic downscaling by reducing surface AMPARs.	Inhibition of PP1 blocks A-induced impairment in hippocampal LTP.	[99, 100]
DHHC2	Translocation of DHHC2 to PSD mediates synaptic scaling by enhancing synaptic targeting of PSD95 and AMPAR.		[86]
Nedd4-1	Upregulation of Nedd4-1 mediates synaptic downscaling by reducing surface AMPAR density.	Nedd4-1 expression is elevated in AD.	[101, 102]
SUMO-1 and Ubc9	SUMOylation of Arc/Arg3.1 mediates synaptic scaling.	SUMO-conjugating enzyme, Ubc9, enhances SUMOylation and rescues A-induced deficits in hippocampal LTP and learning and memory.	[103, 104]
Local dendritic translation of AMPAR
eEF2	Increased eEF2 activity mediates synaptic scaling by stimulating local dendritic synthesis.		[105]
miRNA-92a	Inhibition of miRNA-92A mediates synaptic scaling by stimulating local dendritic synthesis of GluA1.		[106]
Retinoic acid (RA)	Increased RA activity mediates synaptic scaling by stimulating local dendritic synthesis of GluA1 through RA receptor.	RA regulates the expression of APP processing genes, attenuates A deposition, and rescues memory deficits in AD mouse model.	[107–114]
Secreted factors
BDNF	Downregulation of BDNF mediates synaptic scaling.	Downregulation of BDNF levels is associated with the degree of synaptic and cognitive deficits during the progression of AD.	[81, 115–117]
TNFα	TNFα mediates synaptic scaling in primary neuronal culture and visual cortex upon activity deprivation.	TNFα contributes to AD-related brain neuroinflammation and amyloidogenesis via -secretase regulation.	[118–127]
Cell adhesion molecules
3 integrin	Enhanced surface expression of 3 integrin inhibits the small GTPase Rap1 and mediates synaptic scaling by stabilizing synaptic.		[128, 129]
MHC-1	MHC-1 mediates TTX-induced synaptic scaling in hippocampal cultured neurons.		[130]
N-Cadherin	N-Cadherin interaction with -catenin mediates synaptic scaling and downscaling by regulating GluA1-containing AMPARs.	Inhibition of N-Cadherin interaction with -catenin accelerates A-induced synaptic impairments.	[131–135]
EphA4	Increased Eph4 activity mediates synaptic downscaling by stimulating ubiquitin-dependent proteasome degradation of GluA1.	Soluble A oligomers upregulate EphA4 whereas genetic ablation or inhibition of EphA4 prevents hippocampal LTP impairment in AD transgenic model mice.	[136, 137]
Transcriptional regulation
CaMKK-CaMK4	Reduced activity of the CaMKK/CaMK4 signaling pathway mediates synaptic scaling, whereas its stimulation mediates synaptic downscaling.		[138–140]
MSK1	MSK1 mediates TTX-induced synaptic scaling in hippocampal neurons by increasing surface AMPAR density.	MSK1 activity is elevated in AD.	[141, 142]
MeCP2	MeCP2 mediates synaptic scaling in visual cortex upon visual deprivation in vivo.		[143]
Other proteins
Plk2	Increase in Plk2 activity mediates synaptic downscaling.		[144, 145]
Cdk5	Increase in Cdk5 activity mediates synaptic downscaling.	Enhanced Cdk5 activity in AD contributes to Tau phosphorylation and toxicity.	[144, 146]