“Alzheimer’s disease is a progressive neurodegenerative disorder characterized histologically in postmortem human brains by the presence of dense protein accumulations known as amyloid plaques and tau tangles. Plaques and tangles develop over decades of aberrant protein processing, post-translational modification, and misfolding throughout an individual’s lifetime. We present a foundation of evidence from the literature that suggests chronic stress is associated with increased disease severity in Alzheimer’s patient populations. Taken together with preclinical evidence that chronic stress signaling can precipitate cellular distress, we argue that chronic psychological stress renders select circuits more vulnerable to amyloid- and tau- related abnormalities. We discuss the ongoing investigation of systemic and cellular processes that maintain the integrity of protein homeostasis in health and in degenerative conditions such as Alzheimer’s disease that have revealed multiple potential therapeutic avenues. For example, the endogenous cannabinoid system traverses the central and peripheral neural systems while simultaneously exerting anti-inflammatory influence over the immune response in the brain and throughout the body. Moreover, the cannabinoid system converges on several stress-integrative neuronal circuits and critical regions of the hypothalamic-pituitary-adrenal axis, with the capacity to dampen responses to psychological and cellular stress. Targeting the cannabinoid system by influencing endogenous processes or exogenously stimulating cannabinoid receptors with natural or synthetic cannabis compounds has been identified as a promising route for Alzheimer’s Disease intervention. We build on our foundational framework focusing on the significance of chronic psychological and cellular stress on the development of Alzheimer’s neuropathology by integrating literature on cannabinoid function and dysfunction within Alzheimer’s Disease and conclude with remarks on optimal strategies for treatment potential.”

https://pubmed.ncbi.nlm.nih.gov/36268196/

https://www.frontiersin.org/articles/10.3389/fnagi.2022.949361/full

“Neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease. The cannabinoid type 2 receptor (CB₂R) is an emerging target for neuroinflammation and therapeutics of Alzheimer’s disease. Here, we aim to assess the alterations in brain CB₂R levels and evaluate novel CB₂R imaging tracers in the arcAß mouse model of Alzheimer’s disease amyloidosis. Immunohistochemical staining for amyloid-ß deposits (6E10), microgliosis (anti-Iba1 and anti-CD68 antibodies), astrocytes (GFAP) and the anti-CB₂R antibody was performed on brain slices from 17-month-old arcAß mice. Autoradiography using the CB₂R imaging probes [¹⁸F]RoSMA-18-d6, [¹¹C]RSR-056, and [¹¹C]RS-028 and mRNA analysis were performed in brain tissue from arcAß and non-transgenic littermate (NTL) mice at 6, 17, and 24 months of age. Specific increased CB₂R immunofluorescence intensities on the increased number of GFAP-positive astrocytes and Iba1-positive microglia were detected in the hippocampus and cortex of 17-month-old arcAß mice compared to NTL mice. CB₂R immunofluorescence was higher in glial cells inside 6E10-positive amyloid-ß deposits than peri-plaque glial cells, which showed low background immunofluorescence in the hippocampus and cortex of 17-month-old arcAß mice. Ex vivo autoradiography showed that the specific binding of [¹⁸F]RoSMA-18-d6 and [¹¹C]RSR-056 was comparable in arcAß and NTL mice at 6, 17, and 24 months of age. The level of Cnr2 mRNA expression in the brain was not significantly different between arcAß and NTL mice at 6, 17, or 24 months of age. In conclusion, we demonstrated pronounced specific increases in microglial and astroglial CB₂R expression levels in a mouse model of AD-related cerebral amyloidosis, emphasizing CB₂R as a suitable target for imaging neuroinflammation.”

https://pubmed.ncbi.nlm.nih.gov/36248003/

https://www.frontiersin.org/articles/10.3389/fnagi.2022.1018610/full