Preclinical studies have demonstrated that rolipram alleviates memory deficits and depression-like behavior by reducing the amyloid-β burden, tau phosphorylation, neuroinflammation, apoptosis, and neuron loss via the activation of cAMP/PKA and cAMP/EPAC/ERK signaling pathways [50]; roflumilast (another PDE4 inhibitor) leads to the accumulation of cAMP and subsequent increases in pCREB, BDNF, and the ratio of Bcl2/Bax in the brain, which can improve learning and memory function and attenuate depression-like behavior in AD mice [51]. Here, BDNF is linked to major depressive disorder.