The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

Table 1

The effects of AMPK activators on β-amyloidopathy.

AD biomodel	AMPK activator used	Main actions of AMPK activator observed	Mechanism of anti- or pro-Aβ effect	Ref.
High-cholesterol-fed old mice	Quercetin	(i) Quercetin significantly activated AMPK, reduced BACE1 enzyme, lowered Aβ deposit, and improved behavioral performance; (ii) The neuroprotective effects were reversed with compound C (CC) (AMPK inhibitor)	Decrement in BACE1 enzyme expression	[53]
N2a/APP695sw cell lines	Berberine	(i) Reduced BACE1 expression and Aβ deposit; (ii) AMPK activation increased; (iii) Action reversed with compound CC	Decrement in BACE1 enzyme expression	[55]
APP/PS1 transgenic mice and HEK293 and N2a cell lines	Resveratrol	(i) Reduced Aβ deposition both in vitro and in vivo; (ii) Genetic activation of AMPK reduced Aβ whereas genetic inhibition of AMPK increased Aβ; (iii) Autophagy inhibitor, chloroquine, increased Aβ; (iv) Effects of resveratrol were reversed with CC	Activation of autophagic processes	[52]
db/db mice and high glucose-cultured HT22 cells	Metformin	(i) Increased AMPK activation and reduced Aβ & p-tau; (ii) Increased autophagy marker, LC3-II; (iii) Effect was reversed with CC and chloroquine (autophagy inhibitor); (iv) Genetic suppression of autophagy reversed the effect of metformin	Activation of autophagic processes	[71]
N2aSwe cells	Cilostazol	(i) Increased P-AMPK and reduced Aβ; (ii) Enhanced autophagic marker; (iii) Effects were reversed with CC and bafilomycin A1 (autophagy inhibitor)	Activation of autophagic processes	[73]
AβPPswe/PSEN1dE9 mice model	AICAR and rosiglitazone	(i) AMPK and IDE downregulated and Aβ increased in the untreated AβPPswe/PSEN1dE9 mice; (ii) AICAR and RSZ increased IDE expression decreased Aβ level	Increase in the expression of IDE	[74]
Astrocytes from newborn mice	Simvastatin	(i) Increased IDE expression and Aβ degradation; (ii) Bacitracin A, an IDE inhibitor, reversed the effect on Aβ; (iii) 3-MA (autophagy inhibitor) and CC reversed the effect of simvastatin on IDE level	Increase IDE expression by autophagy-based secretory pathway	[75]
SH-SY5Y cell lines and Tg6799 AD mice model	Metformin	(i) Increased β- & γ-secretase cleavage of APP and Aβ deposit; (ii) Abnormal autophagic vacuole accumulation; (iii) Effect was fully reversed with CC but partially reversed with 3-MA	Excessive autophagy mediated increase Aβ level	[76]
N2a695 cells	Metformin	(i) Increased BACE1 expression and Aβ generation; (ii) BACE1 mRNA increased; (iii) Effect was reversed with CC	AMPK activates the transcription of BACE1 mRNA	[77]