Table 1. Putative mechanisms underlying homeostatic failures in early AD.

Molecular target	Mode of action	Relevance to neural homeostasis	Relevance to AD
Presenilin 1	Catalytic subunit of γ-secretase complex Regulation of Ca2+ release from ER	PS1 deletion and early-onset AD M146V PS1 mutation disrupt synaptic scaling	Target of the majority of early-onset AD mutations; the last step in the APP cleavage, determines the length of Aβ and its biophysical properties
BACE1	secretase cleaving APP at β site	BACE1 KO mice display lack of synaptic scaling to visual experience in primary sensory cortex and increased excitatory basal synaptic transmission	APP processing, Aβ production
REST	Transcriptional repressor of neuronal genes during embryonic development	Reduction in excitatory presynaptic strength and in intrinsic excitability to hyperactivity	Its expression is downregulated in MCI and AD, in comparison to normal aging
TNF-α	Releasable by glia cytokine	Postsynaptic up-scaling to inactivity	Increases Aβ production and inhibits the secretion of sAPP Increases BACE1 expression and suppresses Aβ degradation by microglia
BDNF	Activity-dependent, neuron-derived releasable modulator	Postsynaptic scaling and E/I balance Presynaptic adaptation	Early BDNF treatment ameliorates neuronal loss in AD mouse model Interaction between BDNF and APOE polymorp hism affects memory decline in preclinical AD
CDK5	Proline-directed serine/threonine kinase	Synaptic scaling, presynaptic adaptation	CDK5 hyperactivation promotes neurodegeneration
Arc	Immediate early gene product	Synaptic scaling	Regulates activity-dependent Aβ production Reduction of Arc mRNA in the dentate gyrus of AD mice Deregulation of Arc in the vicinity of amyloid plaques disrupts responses to visual stimuli in the visual cortex
NPTX2	Immediate early gene product	NPTXs regulate synaptic scaling of excitatory synapses on PV interneurons	NPTX2 is downregulated in human AD brains and reduction in its expression contributes to aberrant brain activity in AD model mice
mTOR	serine/threonine protein kinase	TSC-mTOR signaling regulates inhibition-excitation balance and firing rate without altering homeostatic responses mTOR regulates presynaptic homeostatic adaptations	Genetic and pharmacological reduction of mTOR signaling ameliorates AD-related pathology and cognitive decline in transgenic AD models
CaMKK2	Ca2+/calmodulin-dependent and serine/threonine protein kinase	STO-609, a CaMKK2 inhibitor, occludes synaptic scaling	STO-609, a CaMKK2 inhibitor, rescues Aβ-induced spine loss
CaMKII	Ca2+-calmodulin-dependent kinase II	Presynaptic and postsynaptic adaptations	p(T286)-αCaMKII is reduced at synaptic locations in hippocampus of AD patients and the degree of p(T286)-αCaMKII loss at synaptic locations correlates with severity of the disease
CaN	Calcineurin, Ca2+-calmodulin-dependent protein phosphatase	Inhibition of CaN activity causes homeostatic synaptic plasticity via retinoic acid	CaN is hyperactivated in AD
Voltage-gated calcium channels	Ion channel	L-type VGCC mediates presynaptic adaptation and postsynaptic scaling	APP regulates L-type VGCC in interneurons
RyR	Ca2+ release from ER	Synaptic scaling	Increase in RyR-mediated Ca2+ release from ER causes dysregulation of Ca2+ homeostasis in AD models
STIM2-SOC-CaMKII	Ca2+ homeostasis	Spine stability	Downregulation of STIM2 causes spine loss in AD mice
Retinoic acid	Transcriptional activator during brain development, synaptic strength modulation	Synaptic scaling	Retinoic acid rescues AD-like pathology in mouse model
GABA(B)R	GPCR	presynaptic and postsynaptic adaptations, firing rate homeostasis	APP is a core molecule of the presynaptic GABA(B)R macromolecular complex Regulates the Aβ40/42 ratio during spike bursts
Adenosine receptors	GPCR	Sleep homeostasis, anti-epileptic effect by increased extracellular adenosine	A2AR are overexpressed in the hippocampus of AD patients and AD mice, mediate LTP and memory impairments A1R regulates the Aβ40/42 ratio during spike bursts

See Supplementary Table 1 for supporting references.