Table 1.

Astrocytic therapeutic targets and molecules used in preclinical studies of AD. In the present table only molecules and drugs (in alphabetic order) that were probed in AD models (i.e., amyloidosis, tauopathy or transgenic animals) and also, that modulate directly or indirectly the astrocyte activity, were included.

Reference	Therapeutic Agent	Astrocytic Target and Mechanism	AD Model	Therapeutic Effects
[155]	1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU)	Blocks astroglial sEH up-regulation, suppression of microglial reactivity through astrocyte-microglia	5xFAD mice	Reduction in proinflammatory gene expression, reversion of immune pathways dysregulation, reduction in gliosis, reduction in number and size of Aβ plaques, cognitive improvement (object recognition test and fear conditioning paradigm)
[370]	17-β-estradiol	Increases astrocytic glutamate uptake by an unknown mechanism that appears to be independent of estrogen receptors Increases expression of GLT-1 and GLAST in astrocytes	AD Human astrocytes	Increment glutamate reuptake in astrocytes
[337]	Cannabidiol (CBD)	Reduces GFAP, IL-1β and iNOS expression in mice exposed to Aβ1–42 Reduces Aβ-generated reactive gliosis	3–5-month-old C57BL/6J mice	Reduces neuroinflammation. Delays onset and progression of Aβ neurotoxicity
[213,219]	Ceftriaxone	IncreaseGLT-1 expression, glutamine synthetase and N glutamine transporter 1	APP/PS1 mice 3xTg-AD mouse model	Decreases cognitive impairment. Promotes the glutamate-glutamine cycle. Reduces tau pathology
[167]	Cornuside	AKT/Nrf2/NF-κB pathway and reduction in proinflammatory cytokines	3xTg-AD mice	Prevention of cognitive impairment. Anti-amyloid. Reduction in tau phosphorylation Anti-inflammatory (reducing IL-1β, IL-6, TNF-α levels) Antioxidant
[137]	Daphnetin	Inhibits STAT3 phosphorylation at Ser727. Decreases astrogliosis (GFAP expression)	APP/PS1 mice	Reduces area and amount of Aβ deposition, decreases the soluble Aβ1–40 and Aβ1–42.
[233]	Dymethyl fumarate	Reduction in GFAP reactivity. Reduction in NF-κB-mediated inflammatory response. Activation of AMPK/SIRT-1 & AKT/CREB/BDNF hubs	D-galactose (D-Gal) administered to ovariectomized (OVX) female rats (postmenopausal AD model)	Ameliorated memory deficits. Anti-inflammatory. Antioxidant effects (via SOD and GSH). Reduction in tauo-/amyloidopathy
[203,204]	Edaravone	Attenuation of endothelium/astrocyte unit dysfunction. Reduction in astrocytosis (GFAP reactivity)	APP23 rodents associated with brain chronic hypoperfusion APPswe/PS1 mice	Reduction in oxidative stress and neuroinflammation. Improved damaged myelin (enhancing oligodendrocytes). Inhibition of Aβ aggregation and reduction in tau hyperphosphorylation
[305]	Epigallocatechin gallate	Increased expression of NEP	Cultured rat astrocytes treated with EGCG	Increased degradation of exogenous Aß
[252]	Gemfibrozil + Retinoic acid	PPARα-dependent pathway, low-density lipoprotein receptor, transcription factor EB	5xFAD mice	RA switched to a neuroprotective state, lowered Aβ in brain, increased lysosomal astrocytic activity, increased autophagic flux, improved spatial learning and memory, enhancement in cognitive function, and reduction in Aβ plaques in hippocampus
[371]	Homoharringtonine	STAT3 signalling in glial cells Increases SOCS3 expression in the hippocampus.	APP/PS1 Mice	Alleviates cognitive deficits. Reduces accumulation of Aβ1–40 and Aβ1–42 in both soluble and insoluble forms. Attenuates synaptic function impairment. Suppresses STAT3 activation and reduces neuroinflammation
[328,329]	Hyperforin	TRPC6 agonist that stimulates activity of the nSOC pathway in the spines Regulates the Akt-GSK3β signaling pathway	APP knock-in and presenilin mouse models	Increases intracellular calcium levels, reduces astrogliosis, disaggregates Aβ aggregates, rescues mushroom spine loss Reduces tau phosphorylation and Aβ1–42 production in PC12 cells
[96]	IL-3	Astrocytic IL-3 induces microglia activation and instructs it to clear aggregates of Aβ and tau.	5xFAD mice	Allows microglia to clear aggregates of Aβ and tau. Reduced memory decline and Aβ load
[140,141]	Kaempferol	Complement C3 and STAT 3 pathways	AD model induced by ICV streptozotocin in Wistar rats	Prevents the activation of complement C3 protein and the generation of neurotoxic astrocytes. Antiamiloid, antioxidative (increased SOD and GSH levels) and anti-inflammatory mechanisms
[298]	L-3-n-butylphthalide	AQP4	APP/PS1 mice	Reduce Aβ deposition and enhance perivascular localization of AQP4.
[129]	LDN/OSU-0212320	Increases EAAT2 function	APPswe mice Primary neuron and astrocyte mixed culture	Reduce cognitive impairment and amyloid burden. Prevent Aβ25–35 oligomer–induced toxicity
[228]	Levetiracetam	Astrocytic SV2A	Primary cultures of human astrocytes exposed with oligomeric Aβ1–42	Reduction in Aβ-induced glutamate release, reduction in gliotransmission-mediated excitation
[346]	Melatonin	Inhibition of Notch1 signalling pathway	Mice ICV injection with Aβ1–42	Improved synaptic function, attenuation of astrogliosis and enhanced spatial memory performance, decrease in GFAP expression
[173,174]	MFG-E8	Downregulation of NF-κB and upregulation of PI3K-Akt	Aβ1–42-activated microglia-conditioned medium to induce astrocytic activation Neuronal/glial mixed culture exposed to Aβ1–42	Anti-inflammatory effects on astrocytes (modulation in IL-1α, TNF, and C1q) Increase microglial endocytosis of Aβ
[147]	Minocycline	Tetracycline antibiotic-protein synthesis inhibitor and increases expression of anti-inflammatory genes	htau mouse AD model	Decrease in astrocytic and caspase-3 activation. Reduction in neuronal loss. Reduce the number of RA, decreases the formation of abnormal tau species and attenuated the production of proinflammatory cytokines
[342]	MRS2179	P2Y1R antagonist	Mice with human KM67/671NL mutation in APP and human L166P-mutated PS1	Increase density and branches length of astrocytic process and points of terminal process close to senile plaques. Preserve structural synaptic integrity
[295]	n-3 polyunsaturated fatty acids (PUFA)	AQP4	fat-1 mice C57BL/6 (ICV Aβ injection)	Promote interstitial Aβ clearance. Inhibit astrocyte activation and protect the AQP4 polarization
[308,309]	NB-02 (previously known as DA-9803)	Mechanism of action under study. Authors suggest that it could be acting by decreasing Aβ oligomerization and production while increasing clearance.	APP/PS1 mice, 5xFAD mice	Halts amyloid plaque deposition, preserves neuronal calcium homeostasis, restores spine density, alters astrocytic morphology, induces a phagocytic state in microglia
[322,323,324]	NPS2143 (CaSR negative allosteric modulator)	CaSR signaling secretion of proinflammatory agents Suppresses astrocytic Aβ1–42 by CaSR signaling.	Aβ25–35-exposed human cortical astrocytes Normal human adult astrocytes, fAβ25–35-treated astrocytes, HC-1A neurons in vitro	Reduces neuroinflammation and amyloidosis. Reduces intracellular accumulation and release of p-tau. Suppresses the release of IL-6, RANTES, ICAM-1 and MCP-2.
[189]	Phloroglucinol	Inhibits the generation of ROS	Oligomeric forms of Aβ1–42 in astrocyte cultures	Enhancing antioxidant enzymes expression such as SOD and GSH. Inhibits astrocytes activation induced by Aβ
[301]	Pioglitazone	Increased LRP1 expression	Senescence-accelerated mouse prone-8 (SAMP8) mice model	Reduction in Aß deposits and Aß1–40 levels improved performance in water maze test
[211]	Riluzole	Increase EAAT2 expression	APPswe/PS1dE9 mice	Prevent cognitive impairment and synaptic plasticity changes induced by early stress
[236]	Roscovitine	CDK inhibitor with affinity for CDK5	SAMP8 mice	Reverses morphological changes produced by glutamate excitotoxicity
[132]	SH-4-54 (STAT3 phosphorylation site inhibitor)	C3aR1-STAT3 signaling mediated astrogliosis and astrocyte reactivity	PS19 mice	Reduction in neuroinflammation and partial rescue of tau pathology
[307]	Sirtuin 1 (SIRT 1)	Promotes oligomeric Aß degradation in astrocytes by deacetylation of lysosome-related proteins and upregulation of total lysosome number	Astrocyte culture of Sprague Dawley rats cortex samples.	Reduction in Aß deposits
[159,163,165]	Sulforaphene	Inhibition of NF-κB and stimulation of Nrf2 pathways	AD-Like pathology model induced by streptozotocin and N2a/APPswe cells	Anti-inflammatory and antioxidant effects. Inhibited the phosphorylation of tau protein and improved cognitive deficit in memory function.
[246,247]	Taurine	Produced and released as gliotransmitter by astrocytes. Activates GABAA and glycine receptors, and serves as GABAB agonist	APP/PS1 transgenic AD mouse	Homeostatic and neuroprotective effects. Regulates intracellular calcium levels, binds to oligomeric Aβ and helps to decrease tau phosphorylation
[263]	TO901317	Astrocytic LXR agonist Increase ABCA1 and APOE expression in astrocytes	APP/PS1 mice	Increase phagocytosis of Aβ by microglial activity. Improve spatial learning
[326,330,331]	Tetrahydroperforin (IDN5607)	TRPC6 agonist that acts by modulating Aβ production, interacting with APP and C99, and blocking the cleavage of C99 by the γ-secretase	APPswe and PS-1dE9 mouse models	Prevents RA inflammatory response, decreases large Aβ deposits., reduces damage caused by oxidative stress, alleviates memory decline
[336]	WIN 55,212-2	CB1 and CB2 receptors	Astrocytes exposed to Aβ1–42	Prevented the elevation of TNF and IL-1β, p-65, COX-2 and iNOS proteins. Increased cell viability