I graduated in Biochemistry at Victoria University, New Zealand and obtained a Ph.D. in Pathology at Otago University, New Zealand in 1987. After post-doctoral research at Harvard Medical School I became Instructor and then Assistant Professor in the Department of Psychiatry, Harvard Medical School, where I first developed my interest in retinoic acid in the developing central nervous system. After working at the University of Massachusetts Medical School, Worcester, MA as Associate Professor in Cell Biology, I moved to the University of Aberdeen in 2006. There I was co-director of the Institute of Medical Sciences until 2015. My research into retinoic acid continues with a focus on its function in the hypothalamus as well as its potential to protect in neuropsychiatric and neurodegenerative disorders, the latter including Alzheimer’s and motor neuron disease.
CNS Vitamin A Research Laboratory
We all grow up with the idea that vitamins are good for us. Certainly, we will become very sick if deficient. However, too much of a good thing can be just as bad as deficiency. Our laboratory investigates why vitamin A is essential for the brain, but also why too much can be harmful. This research uses in-vitro cell lines, studies the brains of mice and rats as well as translating this research to humans. Working in the laboratory are, sitting from left to right Peter Imoesi (PhD student), Patrick Stoney (post-doc, now at the Okinawa Institute of Science and Technology, Japan), Peter McCaffery (PI), Anna Ashton (PhD student), Thabat Khatib (PhD student) and standing Reem Bu Saeed (PhD student).
To HEAR some our research go to Naked Scientist "Science in Scotland" podcast.
To READ some more of our views on nutrients and vitamins head to "The Conversation".
To YOUTUBE view a clip of one of our projects head here
What is vitamin A and what does it do?
Vitamins are compounds in food that, in just small amounts, are required for growth and maintaining good health. Vitamin A is a lipid, often in the chemical form retinol, required for the function of the brain, as well as many other organs. It can be converted to an acidic form called retinoic acid (see below). For many of Vitamin A’s functions its conversion to retinoic acid is essential. Cells that require retinoic acid capture vitamin A from the circulation and contain the enzymes that convert it to retinoic acid.
(1) Retinoic acid in the pineal gland (Anna Ashton)
The main function of the pineal gland is to produce melatonin – the ‘hormone of the night’, which is released during darkness and has numerous roles including regulation of circadian rhythms. Previous studies demonstrate that vitamin A is important for melatonin production, as vitamin A deficiency leads to a significant reduction in the night-time melatonin peak. Despite this, the role of vitamin A and retinoic acid in the pineal gland has been scarcely investigated. We have found that the rodent pineal gland is capable of producing retinoic acid, and our findings reveal some intriguing changes in signalling that suggest it may also be subject to a day/night rhythm. We are currently investigating the role of retinoic acid in the regulation of melatonin production, specifically looking at transcriptional regulation of the rate-limiting enzyme for melatonin synthesis, AANAT.
Raldh3 gene expression changes over the 24 hour light/dark cycle. Raldh3 is one of the enzymes required for the production of retinoic acid from vitamin A.
The pineal gland is under the control of the central circadian clock, located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Light regulates this system through direct innervation of the SCN from the retina. (adapted from Bustos et al., 2011).
(2) Two lipids signalling in the brain: retinoic acid and the cannabinoids (Reem Bu Saeed)
Lipids play a central role in the brain’s actions and make up 60% of it’s constituents. The role of lipids include acting as signalling molecules to control function, both during development and within the mature brain. Two major lipid-signalling routes that have been described are the endocannabinoid eCB and retinoid signalling systems, both of which have essential roles to control neuroplasticity; cross talk between the two may have a profound effect on the brain. My project investigates the relationship between the retinoid and endocannabinoid signalling pathways: retinoic acid can regulate cannabinoid receptor expression in brain cells as well as the metabolic enzyme diacylglycerol lipase. This work demonstrates that the eCB signalling system and retinoid system may have primary or secondary influences on one another in the central nervous system.
Retinoic acid and cannabinoid signalling in P19 cells
(3) Triggering genomic versus non-genomic retinoid signalling pathways as a treatment for Alzheimer’s disease (Thabat Khatib)
This project focuses on a set of new discoveries we have made on molecules that bind to a group of receptors called the RARs (retinoic acid receptors). They have been known for many years and the RAR activating molecules are in use for diseases of the skin as well as treatment of cancer. However our new discoveries suggest a function for these molecules in the treatment of neurodegenerative diseases like Alzheimer’s disease.
Retinoic acid is the molecule in the body that activates the RARs. Strong support for the idea that retinoic acid would help reverse cognitive decline in neurodegenerative disease came from the findings that local retinoic acid levels decline in the ageing human and rodent brain. Retinoic acid supports neuronal survival and neuroplasticity, essential for learning and memory, and application of retinoic acid to aged animals reverses this decline. Several laboratory studies have indicated that retinoic acid is protective for Aβ neurotoxicity, a major cause of neuronal death in Alzheimer’s disease. Boosting the retinoic acid signal with synthetic ligands for RARs improves cognition in mice genetically altered to have Alzheimer’s disease, removing Aβ in both neurons and microglia. Importantly, retinoic acid has an efficacious effect in many types of Alzheimer’s disease, for instance improving cognition and providing anti-inflammatory action in a diabetic model of Alzheimer’s disease.
A collaboration has been set up with Prof Andrew Whiting, a chemist at Durham University, to study the new RAR activating molecules he has discovered. It is believed that the way in which these trigger the RARs, in ways known as “genomic” versus “non-genomic” activity, correlate with their biological action relevant to treatment of Alzheimer’s and other neurodegenerative diseases. The biological actions investigated include the ability of RAR activating molecules to induce neurons to form long processes (axons and dendrites) as a sign of neuronal repair. Also investigated are the effects of these RAR activating molecules on gene expression as markers indicating beneficial amyloid processing, anti-inflammatory action and neuroprotection. The project will point the direction to future new treatments for Alzheimer’s disease, involving retinoic acid and other RAR activating molecules. It will improve the likelihood of identification of drugs that are beneficial in AD and other neurodegenerative disorders.
Retinoids inducing neurite outgrowth in SH-SY5Y cells
(4) How vitamin A homeostasis may be controlled by the hypothalamus (Peter Imoesi)
Vitamin A (retinol) occurs in animals as esters of higher fatty acid which is an essential constitute of mammalian diet. Basically vitamin A is derived from carotenoids which are plant pigments or the liver of animals. Essentially dietary retinol is transported in circulation and bound to retinol binding protein (RBP). Subsequently, with the aid of RBP receptor stra6, cells are able to recruit and transport retinol to the cytosol. In the cytosol retinol is bound to cellular retinol binding protein (CRBP) and through various enzymatic processes retinol is converted to retinoic acid in the nucleus to initiate gene transcription. Retinol is maintained at a precise concentration of 1µM in plasma despite the slight increase of dietary intake. However, how the body is able to maintain this concentration is relatively unknown. Previous research as implicate the hypothalamus as the central control of body homeostasis for instance glucose. My research is to determine how vitamin A (retinol) homeostasis is controlled by the hypothalamus. To investigate this, rats will be injected with retinoic acid (RA) the active metabolite of retinol to the hypothalamus using a stereotactic procedure and subsequently systemic increase or decrease of RA will be measured over time.
Tanycytes lining the wall of the third ventricle (3V) of the hypothalamus may be a key cell in the control of vitamin A homeostasis
Wellcome, BBSRC, Tenovus, Autism Speaks, The Royal Society and The Royal Society of Edinburgh
- Further Info
Potential PhD Projects
Title: "Vitamin A and retinoic acid as master regulators of the HPA axis."
Our research has revealed new functions for retinoic acid in both the hypothalamus and pituitary and this project will unify these findings to determine how retinoic acts in the Hypothalamus Pituitary Adrenal (HPA) axis.? This will help to find, for instance, how vitamin A may influence energy balance and weight.? It may also reveal how the retinoic acid based drugs used to treat acne may influence depression through their action on the HPA axis.
Title: "Vitamin A as a cure for the ageing brain?"
A number of studies have pointed to the beneficial cognitive effects in the aged of vitamin A and retinoic acid.? The mechanisms behind this are a puzzle but our research points to a decline in the aged human brain's capacity to synthesize retinoic acid.? This project will investigate the reasons behind this, the consequences for the brain and retinoic acid as a "cognitive enhancer".
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- Khatib, T, Chisholm, DR, Whiting, A, Platt, B & McCaffery, P 2020, 'Decay in Retinoic Acid Signaling in Varied Models of Alzheimer’s Disease and In-Vitro Test of Novel Retinoic Acid Receptor Ligands (RAR-Ms) to Regulate Protective Genes', Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 935-954. [Online] DOI: https://doi.org/10.3233/JAD-190931
- Kouchmeshky, A, Goodman, T, Goodman, T & McCaffery, P 2020, Tissue localization of retinoic acid receptor (RAR) active drugs. in E Pohl (ed.), Methods in Enzymology. vol. 637, Methods in Enzymology, vol. 637, BMJ Publishing Group, London, pp. 513-538. [Online] DOI: https://doi.org/10.1016/bs.mie.2020.03.012
- Kouchmeshky, A & McCaffery, P 2020, Use of fixatives for immunohistochemistry and their application for detection of retinoic acid synthesizing enzymes in the central nervous system. in E Pohl (ed.), Methods in Enzymology. vol. 637, Methods in Enzymology, vol. 637, ELSEVIER ACADEMIC PRESS INC, pp. 119-150. [Online] DOI: https://doi.org/10.1016/bs.mie.2020.03.010
- Khatib, T, Whiting, A, Chisholm, DR, Redfern, C, Muller, B & McCaffery, P 2019, 'A Bioluminescence Reporter Assay for Retinoic Acid Control of Translation of the GluR1 Subunit of the AMPA Glutamate Receptor', Molecular Neurobiology, vol. 56, no. 10, pp. 7074-7084. [Online] DOI: https://doi.org/10.1007/s12035-019-1571-9
- Khatib, T, Marini, P, Nunna, S, Chisholm, DR, Whiting, A, Redfern, C, Greig, IR & McCaffery, P 2019, 'Genomic and non-genomic pathways are both crucial for peak induction of neurite outgrowth by retinoids', Cell Communication and Signaling, vol. 17, 40. [Online] DOI: https://doi.org/10.1186/s12964-019-0352-4
- Lee, LMY, Tam, STK, McCaffery, PJ & Shum, ASW 2019, Highly Sensitive Quantitative Determination of Retinoic Acid Levels, Retinoic Acid Synthesis, and Catabolism in Embryonic Tissue Using a Reporter Cell-Based Method. in SK Ray (ed.), Retinoid and Rexinoid Signaling. vol. 2019, Methods in Molecular Biology, vol. 2019, HUMANA PRESS INC, pp. 181-192. [Online] DOI: https://doi.org/10.1007/978-1-4939-9585-1_13
- Imoesi, PI, Bowman, EE, Stoney, PN, Matz, S & McCaffery, P 2019, 'Rapid Action of Retinoic Acid on the Hypothalamic Pituitary Adrenal Axis', Frontiers in Neuroscience, vol. 12, 259. [Online] DOI: https://doi.org/10.3389/fnmol.2019.00259
- Whiting, A, Chisholm, D, Valentine, R, Greig, IR, McCaffery, PJA & Alkhatib, T Apr. 18 2019, Synthetic Retinoids for Use in RAR Mediated Conditions, Patent No. WO2017174999, IPC No. C07C 63/66, A61K 31/192, A61K 31/203, A61P 25/28, C07D 209/82, C07D 215/06.
- Haffez, H, Khatib, T, McCaffery, P, Przyborski, S, Redfern, C & Whiting, A 2018, 'Neurogenesis in Response to Synthetic Retinoids at Different Temporal Scales', Molecular Neurobiology, vol. 55, no. 3, pp. 1942-1950. [Online] DOI: https://doi.org/10.1007/s12035-017-0440-7
- Ashton, A, Stoney, PN, Ransom, J & McCaffery, P 2018, 'Rhythmic Diurnal Synthesis and Signaling of Retinoic Acid in the Rat Pineal Gland and Its Action to Rapidly Downregulate ERK Phosphorylation', Molecular Neurobiology, vol. 55, no. 11, pp. 8219-8235. [Online] DOI: https://doi.org/10.1007/s12035-018-0964-5