Some of the most prevalent neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease, are proteinopathies characterized by the accumulation of specific protein aggregates in the brain. Such misfolded protein aggregates can trigger modulation of the innate and adaptive immune systems and subsequently lead to chronic neuroinflammation that drives the onset and progression of neurodegenerative diseases. Since there is still no effective disease-modifying treatment, new therapeutic targets for neurodegenerative proteinopathies have been sought. The endocannabinoid system, and in particular the cannabinoid CB2 receptors, have been extensively studied, due to their important role in neuroinflammation, especially in microglial cells. Several studies have shown promising effects of CB2 receptor activation on reducing protein aggregation-based pathology as well as on attenuating inflammation and several dementia-related symptoms. In this review, we discuss the available data on the role of CB2 receptors in neuroinflammation and the potential benefits and limitations of specific agonists of these receptors in the therapy of neurodegenerative proteinopathies.

In the last decade, increasing evidence has emerged linking alterations in the brain-derived neurotrophic factor (BDNF) expression with the development of Alzheimer’s disease (AD). Because of the important role of BDNF in cognition and its association with AD pathogenesis, the aim of this study was to evaluate the potential difference in plasma BDNF concentrations between subjects with mild cognitive impairment (MCI; N = 209) and AD patients (N = 295) and to determine the possible association between BDNF plasma levels and the degree of cognitive decline in these individuals. The results showed a significantly higher (p < 0.001) concentration of plasma BDNF in subjects with AD (1.16; 0.13–21.34) compared with individuals with MCI (0.68; 0.02–19.14). The results of the present study additionally indicated a negative correlation between cognitive functions and BDNF plasma concentrations, suggesting higher BDNF levels in subjects with more pronounced cognitive decline. The correlation analysis revealed a significant negative correlation between BDNF plasma levels and both Mini-Mental State Examination (p < 0.001) and Clock Drawing test (p < 0.001) scores. In conclusion, the results of our study point towards elevated plasma BDNF levels in AD patients compared with MCI subjects, which may be due to the body’s attempt to counteract the early and middle stages of neurodegeneration.

Dementia is a syndrome of global and progressive deterioration of cognitive skills, especially memory, learning, abstract thinking, and orientation, usually affecting the elderly. The most common forms are Alzheimer’s disease, vascular dementia, and other (frontotemporal, Lewy body disease) dementias. The etiology of these multifactorial disorders involves complex interactions of various environmental and (epi)genetic factors and requires multiple forms of pharmacological intervention, including anti-dementia drugs for cognitive impairment, antidepressants, antipsychotics, anxiolytics and sedatives for behavioral and psychological symptoms of dementia, and other drugs for comorbid disorders. The pharmacotherapy of dementia patients has been characterized by a significant interindividual variability in drug response and the development of adverse drug effects. The therapeutic response to currently available drugs is partially effective in only some individuals, with side effects, drug interactions, intolerance, and non-compliance occurring in the majority of dementia patients. Therefore, understanding the genetic basis of a patient’s response to pharmacotherapy might help clinicians select the most effective treatment for dementia while minimizing the likelihood of adverse reactions and drug interactions. Recent advances in pharmacogenomics may contribute to the individualization and optimization of dementia pharmacotherapy by increasing its efficacy and safety via a prediction of clinical outcomes. Thus, it can significantly improve the quality of life in dementia patients.

Background/Objectives: Beneficial effects of neurosteroid dehydroepiandrosterone sulphate (DHEAS) on cognition, emotions and behavior have been previously reported, suggesting its potential in the prevention and treatment of various neuropsychiatric and neurodegenerative disorders, including Alzheimer’s disease (AD). This study aimed to investigate the potential neuroprotective actions of DHEAS against Aβ toxicity in both cellular and animal models of AD. Methods: After optimizing the AD model in vitro, we investigated the DHEAS effects on the viability and death of primary mouse neurons exposed to toxic Aβ₄₂ oligomers for 24 h. In order to extend our research to an in vivo study, we further tested the acute effects of intraperitoneal DHEAS administration on the Aβ plaque density in different brain regions of 3xTg-AD mice, an animal model of AD. Results: In cell culture, DHEAS hampered the decrease in the neuronal viability caused by toxic Aβ oligomers, primarily by influencing mitochondrial function and apoptosis. DHEAS also counteracted the increase in the mRNA expression of selected genes (PI3K, Akt, Bcl2, Bax), induced in neuronal culture by treatment with Aβ₄₂ oligomers. Obtained data suggested the involvement of mitochondria, caspases 3 and 7, as well as the PI3K/Akt and Bcl2 signaling network in the antiapoptotic properties of DHEAS in neurons. Forty-eight hours after DHEAS treatment, a significantly lower number of Aβ plaques was observed in the motor cortex but not in other brain areas of 3xTg-AD mice. Conclusions: Results indicated potential neuroprotective effects of DHEAS against Aβ toxicity and accumulation, suggesting that DHEAS supplementation should be further studied as a novel option for AD prevention and/or treatment.