Alterations in hippocampal neurogenesis have been recognized as an integral part of Alzheimer&... more Alterations in hippocampal neurogenesis have been recognized as an integral part of Alzheimer's disease. Adult hippocampal neurogenesis is regulated by intrinsic and extrinsic factors; one of them is diet. This review provides an assessment of the current state of the field in hippocampal neurogenesis studies in Alzheimer's disease and focuses on the role of diet. The review highlights some of the key dietary compounds and interventions such as calorie restriction, fat, polyphenols, zinc, folate, alcohol and thiamine, and emphasizes the pathways that they modify.
The regenerative decline of organisms during ageing is linked to the reduced proliferative activi... more The regenerative decline of organisms during ageing is linked to the reduced proliferative activity, impaired function and exhaustion of tissue-specific stem and progenitor cells. Studies using heterochronic parabiosis, involving the surgical attachment of young and old organisms so that they share a common vascular system, have revealed that the systemic environment has a profound effect on stem cell function. In particular, specific youthful rejuvenating circulatory factors reverse age-related declines in stem cell function, whereas the old milieu contains inhibitory factors that impede stem cell function in young animals. Similarly, the effects of certain dietary interventions, namely calorie restriction, also induce a more youthful cellular and molecular phenotype in ageing stem cells throughout the body. Further to this, there are key molecular pathways involved in translating the availability of nutrients into altered stem cell function, including signalling in the insulin and insulin-like growth factor and mechanistic target of rapamycin (mTOR) pathways. In this review, we discuss the potential role of dietary interventions to promote a more rejuvenating systemic milieu in order to enhance stem cell function and promote healthy ageing.
Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among... more Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among these dietary interventions, we here highlight the impact of caloric restriction (CR: a consistent reduction of total daily food intake), intermittent fasting (IF, every-other-day feeding), and diet supplementation with polyphenols and polyunsaturated fatty acids (PUFAs) on markers of brain plasticity in animal studies. Moreover, we also discuss epidemiological and intervention studies reporting the effects of CR, IF and dietary polyphenols and PUFAs on learning, memory, and mood. In particular, we evaluate the gap in mechanistic understanding between recent findings from animal studies and those human studies reporting that these dietary factors can benefit cognition, mood, and anxiety, aging, and Alzheimer's disease-with focus on the enhancement of structural and functional plasticity markers in the hippocampus, such as increased expression of neurotrophic factors, synaptic function and adult neurogenesis. Lastly, we discuss some of the obstacles to harnessing the promising effects of diet on brain plasticity in animal studies into effective recommendations and interventions to promote healthy brain function in humans. Together, these data reinforce the important translational concept that diet, a modifiable lifestyle factor, holds the ability to modulate brain health and function.
Amyotrophic lateral sclerosis is a neuromuscular disease characterized by selective loss of motor... more Amyotrophic lateral sclerosis is a neuromuscular disease characterized by selective loss of motor neurons leading to fatal paralysis. We previously reported a coding mutation in D-amino acid oxidase (R199W DAO) associated with familial amyotrophic lateral sclerosis. DAO metabolizes D-serine, a co-agonist at the N-methyl-D-aspartic acid receptor. We investigated the mechanisms mediating the pathogenic effects of R199W DAO on motor neuron survival and showed that expression of glial R199W DAO is sufficient to induce apoptosis in cocultured motor neurons and this is sensitive to 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, an N-methyl-d-aspartic acid receptor antagonist selective for the D-serine/glycine site. R199W DAO activates protein aggregation and autophagy, which is also sensitive to this antagonist. Using immunocytochemistry, we showed that D-serine and DAO were abundant in spinal cord motor neurons and depleted in amyotrophic lateral sclerosis. In summary, the toxic effects of R199W DAO on motor neurons can be mediated directly by expression in motor neurons or by astrocytes in coculture, R199W DAO promotes autophagy and its pathogenic effects are at least in part mediated via the N-methyl-d-aspartic acid receptor.
Alterations in hippocampal neurogenesis have been recognized as an integral part of Alzheimer&... more Alterations in hippocampal neurogenesis have been recognized as an integral part of Alzheimer's disease. Adult hippocampal neurogenesis is regulated by intrinsic and extrinsic factors; one of them is diet. This review provides an assessment of the current state of the field in hippocampal neurogenesis studies in Alzheimer's disease and focuses on the role of diet. The review highlights some of the key dietary compounds and interventions such as calorie restriction, fat, polyphenols, zinc, folate, alcohol and thiamine, and emphasizes the pathways that they modify.
The regenerative decline of organisms during ageing is linked to the reduced proliferative activi... more The regenerative decline of organisms during ageing is linked to the reduced proliferative activity, impaired function and exhaustion of tissue-specific stem and progenitor cells. Studies using heterochronic parabiosis, involving the surgical attachment of young and old organisms so that they share a common vascular system, have revealed that the systemic environment has a profound effect on stem cell function. In particular, specific youthful rejuvenating circulatory factors reverse age-related declines in stem cell function, whereas the old milieu contains inhibitory factors that impede stem cell function in young animals. Similarly, the effects of certain dietary interventions, namely calorie restriction, also induce a more youthful cellular and molecular phenotype in ageing stem cells throughout the body. Further to this, there are key molecular pathways involved in translating the availability of nutrients into altered stem cell function, including signalling in the insulin and insulin-like growth factor and mechanistic target of rapamycin (mTOR) pathways. In this review, we discuss the potential role of dietary interventions to promote a more rejuvenating systemic milieu in order to enhance stem cell function and promote healthy ageing.
Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among... more Dietary interventions have emerged as effective environmental inducers of brain plasticity. Among these dietary interventions, we here highlight the impact of caloric restriction (CR: a consistent reduction of total daily food intake), intermittent fasting (IF, every-other-day feeding), and diet supplementation with polyphenols and polyunsaturated fatty acids (PUFAs) on markers of brain plasticity in animal studies. Moreover, we also discuss epidemiological and intervention studies reporting the effects of CR, IF and dietary polyphenols and PUFAs on learning, memory, and mood. In particular, we evaluate the gap in mechanistic understanding between recent findings from animal studies and those human studies reporting that these dietary factors can benefit cognition, mood, and anxiety, aging, and Alzheimer's disease-with focus on the enhancement of structural and functional plasticity markers in the hippocampus, such as increased expression of neurotrophic factors, synaptic function and adult neurogenesis. Lastly, we discuss some of the obstacles to harnessing the promising effects of diet on brain plasticity in animal studies into effective recommendations and interventions to promote healthy brain function in humans. Together, these data reinforce the important translational concept that diet, a modifiable lifestyle factor, holds the ability to modulate brain health and function.
Amyotrophic lateral sclerosis is a neuromuscular disease characterized by selective loss of motor... more Amyotrophic lateral sclerosis is a neuromuscular disease characterized by selective loss of motor neurons leading to fatal paralysis. We previously reported a coding mutation in D-amino acid oxidase (R199W DAO) associated with familial amyotrophic lateral sclerosis. DAO metabolizes D-serine, a co-agonist at the N-methyl-D-aspartic acid receptor. We investigated the mechanisms mediating the pathogenic effects of R199W DAO on motor neuron survival and showed that expression of glial R199W DAO is sufficient to induce apoptosis in cocultured motor neurons and this is sensitive to 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, an N-methyl-d-aspartic acid receptor antagonist selective for the D-serine/glycine site. R199W DAO activates protein aggregation and autophagy, which is also sensitive to this antagonist. Using immunocytochemistry, we showed that D-serine and DAO were abundant in spinal cord motor neurons and depleted in amyotrophic lateral sclerosis. In summary, the toxic effects of R199W DAO on motor neurons can be mediated directly by expression in motor neurons or by astrocytes in coculture, R199W DAO promotes autophagy and its pathogenic effects are at least in part mediated via the N-methyl-d-aspartic acid receptor.
Uploads
Papers by Tytus Murphy