Successful and Unsuccessful Brain Aging in Pets: Pathophysiological Mechanisms behind Clinical Signs and Potential Benefits from Palmitoylethanolamide Nutritional Intervention

SIMPLE SUMMARY: Cognitive dysfunction syndrome is a common yet underreported neurodegenerative disorder of elderly dogs and cats and a natural model of human Alzheimer’s disease. The increasingly expanding life expectancy means a larger proportion of affected animals in the coming decades. Although far from being curative, available treatments are more effective the sooner they are started. Educating veterinary practitioners and owners in the early recognition of age-related cognitive dysfunction is thus mandatory. By shedding light on the mechanism underlying the disease, novel and more effective approaches might be developed. Emerging evidence shows that successful and unsuccessful brain aging share a common underlying mechanism that is neuroinflammation. This process involves astrocytes, microglia, and mast cells and has a restorative homeostatic intent. However, for reasons not fully elucidated yet, neuroinflammation can also exert detrimental consequences substantially contributing to neurodegeneration. Here we summarize the evidence accumulated so far on the pathogenic role of neuroinflammation in the onset and progression of age-related neurodegenerative disorders, such as Alzheimer’s disease. The potential benefit of palmitoylethanolamide dietary intervention in rebalancing neuroinflammation and exerting neuroprotection is also discussed. ABSTRACT: Canine and feline cognitive dysfunction syndrome is a common neurodegenerative disorder of old age and a natural model of human Alzheimer’s disease. With the unavoidable expanding life expectancy, an increasing number of small animals will be affected. Although there is no cure, early detection and intervention are vitally important to delay cognitive decline. Knowledge of cellular and molecular mechanisms underlying disease onset and progression is an equally decisive factor for developing effective approaches. Uncontrolled neuroinflammation, orchestrated in the central nervous system mainly by astrocytes, microglia, and resident mast cells, is currently acknowledged as a hallmark of neurodegeneration. This has prompted scientists to find a way to rebalance the altered crosstalk between these cells. In this context, great emphasis has been given to the role played by the expanded endocannabinoid system, i.e., endocannabinoidome, because of its prominent role in physiological and pathological neuroinflammation. Within the endocannabinoidome, great attention has been paid to palmitoylethanolamide due to its safe and pro-homeostatic effects. The availability of new ultramicronized formulations highly improved the oral bioavailability of palmitoylethanolamide, paving the way to its dietary use. Ultramicronized palmitoylethanolamide has been repeatedly tested in animal models of age-related neurodegeneration with promising results. Data accumulated so far suggest that supplementation with ultramicronized palmitoylethanolamide helps to accomplish successful brain aging.