Cognitive-enhancing effects of angiotensin IV

Angiotensin IV is a derivative of the potent vasoconstrictor angiotensin II and it has been shown to enhance acquisition, consolidation and recall in animal models of learning and memory when administered centrally or peripherally. Whether changes in angiotensin IV activity underlie the cognitive effects of those cardiovascular drugs designed to disrupt the peripheral renin-angiotensin system in humans remains undetermined, but angiotensin IV appears to be a worthy candidate for consideration in drug development programmes. The mechanism of action of angiotensin IV is still debated, although its AT4 receptor has been convincingly identified as being insulin-regulated amino peptidase, which is also known as oxytocinase and placental leucine aminopeptidase. It is speculated that angiotensin IV may interact with insulin-regulated amino peptidase to enhance neuronal glucose uptake, prevent metabolism of other neuroactive peptides, induce changes in extracellular matrix molecules, or induce release of acetylcholine and/or dopamine. All of these things may be responsible for the beneficial effects on cognition, but none of them are yet proven. Importantly, strain differences in murine responses to angiotensin IV suggest that some individuals may benefit from drugs targeted to the AT4 receptor whilst others may be refractory. At present it thus appears that those individuals with the poorest baseline cognition may receive greatest benefit, but possible genetic differences in responses to angiotensin IV cannot be ruled-out

Positive Effects of Cholinergic Stimulation Favor Young APOE ε4 Carriers

The potential of putative cognitive-enhancing compounds to improve mental processing both in healthy and vulnerable populations is an area of growing interest to scientific and clinical communities. The possible influence of individual genetic differences on efficacy of these compounds has yet to be considered. We sought to investigate the profile of young-adult apolipoprotein E (APOE) 4 carriers across cognitive domains given that possession of this gene variant increases risk of developing dementia in later life. We also explored whether APOE genotype interacts with the cognitive enhancer, nicotine. A total of 1 mg of the cholinergic agonist nicotine was administered through nasal spray to healthy non-smoking young adults (aged 18-30) with either 3/3 (N29) or 4 (at least one 4 allele, N27) genotype. Participants were matched on age, sex, and IQ in a placebo-controlled, double-blind 2 (drug: placebo, nicotine) × 2 (genotype: 3, 4) between subjects design. Here, we show that, paradoxically, possession of the 4 allele confers a cognitive advantage on tasks mediated by the frontal lobe, and that young carriers of the 4 allele show larger cognitive benefit from procholinergic nicotinic stimulation. These results are the first to show that genetic differences influence the efficacy of a cognitive enhancer