阿茲海默症(Alzheimer's disease, AD)是為一種失智症，也是神經退化性疾病之一，其特徵在於Aβ斑塊沉積和tau蛋白過度磷酸化，形成神經原纖維纏結。研究顯示缺氧會增加Aβ斑塊沈積，惡化阿茲海默症病程。除此之外，缺氧也會造成細胞自噬功能缺陷和神經性發炎，更惡化阿茲海默症程。然而，內源性大麻素系統可增加腦血流量和抗炎作用具有神經保護的機制。研究指出大麻素2型受體(CB2R)活化Beclin-1和LC3II / LC3I蛋白表達，以及下調p62表達，透過調控細胞自噬，減少神經元死亡。但是，在阿茲海默症中，內源性大麻素系統神經保護作用的機制仍不清楚。因此，我們欲探討內源性大麻素系統是否能通過活化細胞自噬來減緩缺氧所造成的損傷。我們的結果顯示，在神經細胞中，不論是正常細胞或過度表達APP695的細胞，缺氧都會增加 BACE1及PSEN1的蛋白質表達，此兩種蛋白為分裂APP和釋放Aβ的主要蛋白酶，並且會導致LC3II / I與p62蛋白質表達增加，產生細胞自噬功能缺陷，而透過細胞自噬活化劑可以減少BACE1蛋白質表達。在星形膠質細胞中，缺氧活化了 CB1R及CB2R的蛋白質表達，活化了內源性大麻素系統的神經保護性。在微膠細胞中，缺氧降低p62蛋白質表達，細胞自噬功能是完好的。因此，在大腦重要的細胞中，缺氧的條件下，主要是透過神經細胞產出Aβ，並且能透過細胞自噬降解，而星形膠質細胞具有神經保護性。

Alzheimer’s disease (AD) is a progressive form of dementia, serving as a neurodegenerative disorder, is characterized by the accumulation of β-amyloid (Aβ) deposition and hyperphosphorylated tau protein aggregation. Previous studies indicated that hypoxia is related to the exacerbate AD progression, increases Aβ plaque and tau phosphorylation formed neurofibrillary tangles. And growing evidence have also demonstrated that deterioration of autophagy dysfunction and neuroinflammation contributes to the hypoxic effect in Alzheimer’s disease. Previous studies showed that the endocannabinoid system increases cerebral blood flow and anti-inflammation. And increasing evidence the endocannabinoid system plays a protective role in the central nervous system, which inducing autophagy to improve the symptoms of neurological diseases. But the mechanisms of the endocannabinoid system neuroprotective effect remains unclear in Alzheimer’s disease. We hypothesized that the endocannabinoid system prevents hypoxic injury via activation of the autophagy mechanism. Our results showed that hypoxia increased the protein expression of β-secretase (BACE1) and γ-secretase (PSEN1), which are the major proteases to cleavage of APP and liberating Aβ peptide. Hypoxia increased the protein expression of LC3II/I ratio and p62, meaning autophagy dysfunction. To activate autophagy decreased the protein expression of β-secretase (BACE1) in neuron cells. Moreover, hypoxia increased the protein expression of CB1R and CB2R, which means neuroprotective effect.

Arain, M., Khan, M., Craig, L., & Nakanishi, S. T. (2015). Cannabinoid agonist rescues learning and memory after a traumatic brain injury. Annals of Clinical and Translational Neurology, 2(3), 289–294. https://doi.org/10.1002/acn3.163
Basavarajappa, B. S. (2007). Critical enzymes involved in endocannabinoid metabolism. Protein and Peptide Letters, 14(3), 237–246. https://doi.org/10.2174/092986607780090829
Belyaev, N. D., Kellett, K. A. B., Beckett, C., Makova, N. Z., Revett, T. J., Nalivaeva, N. N., Hooper, N. M., & Turner, A. J. (2010). The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a {beta}-secretase-dependent pathway. The Journal of Biological Chemistry, 285(53), 41443–41454. https://doi.org/10.1074/jbc.M110.141390
Fakhoury, M. (2018). Microglia and Astrocytes in Alzheimer’s Disease: Implications for Therapy. Current Neuropharmacology, 16(5), 508–518. https://doi.org/10.2174/1570159X15666170720095240
G., Z. J., David, F.-L., Isaac, G.-Y., S., G.-G. M., José, V., Florentino, N., Magdalena, T., C., B. M., Jorge, M., Ignacio, L., & A., M. M. (2012). Cannabinoid Type 2 Receptor Activation Downregulates Stroke-Induced Classic and Alternative Brain Macrophage/Microglial Activation Concomitant to Neuroprotection. Stroke, 43(1), 211–219. https://doi.org/10.1161/STROKEAHA.111.631044
Glick, D., Barth, S., & Macleod, K. F. (2010). Autophagy: cellular and molecular mechanisms. The Journal of Pathology, 221(1), 3–12. https://doi.org/10.1002/path.2697
Gong, C.-X., & Iqbal, K. (2008). Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Current Medicinal Chemistry, 15(23), 2321–2328. https://doi.org/10.2174/092986708785909111
Han, X.-J., Hu, Y.-Y., Yang, Z.-J., Jiang, L.-P., Shi, S.-L., Li, Y.-R., Guo, M.-Y., Wu, H.-L., & Wan, Y.-Y. (2017). Amyloid β-42 induces neuronal apoptosis by targeting mitochondria. Molecular Medicine Reports, 16(4), 4521–4528. https://doi.org/10.3892/mmr.2017.7203
Kocaturk, N. M., & Gozuacik, D. (2018). Crosstalk Between Mammalian Autophagy and the Ubiquitin-Proteasome System. Frontiers in Cell and Developmental Biology, 6, 128. https://doi.org/10.3389/fcell.2018.00128
Lall, R., Mohammed, R., & Ojha, U. (2019). What are the links between hypoxia and Alzheimer’s disease? Neuropsychiatric Disease and Treatment, 15, 1343–1354. https://doi.org/10.2147/NDT.S203103
Lu, H.-C., & Mackie, K. (2016). An Introduction to the Endogenous Cannabinoid System. Biological Psychiatry, 79(7), 516–525. https://doi.org/10.1016/j.biopsych.2015.07.028
Murphy, M. P., & LeVine 3rd, H. (2010). Alzheimer’s disease and the amyloid-beta peptide. Journal of Alzheimer’s Disease : JAD, 19(1), 311–323. https://doi.org/10.3233/JAD-2010-1221
Small, G. W., Kepe, V., Ercoli, L. M., Siddarth, P., Bookheimer, S. Y., Miller, K. J., Lavretsky, H., Burggren, A. C., Cole, G. M., Vinters, H. V, Thompson, P. M., Huang, S.-C., Satyamurthy, N., Phelps, M. E., & Barrio, J. R. (2006). PET of Brain Amyloid and Tau in Mild Cognitive Impairment. New England Journal of Medicine, 355(25), 2652–2663. https://doi.org/10.1056/NEJMoa054625
Sun, X., He, G., Qing, H., Zhou, W., Dobie, F., Cai, F., Staufenbiel, M., Huang, L. E., & Song, W. (2006). Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proceedings of the National Academy of Sciences of the United States of America, 103(49), 18727–18732. https://doi.org/10.1073/pnas.0606298103
Wu, Q., Zhang, M., Liu, X., Zhang, J., & Wang, H. (2020). CB2R orchestrates neuronal autophagy through regulation of the mTOR signaling pathway in the hippocampus of developing rats with status epilepticus. International Journal of Molecular Medicine, 45(2), 475–484. https://doi.org/10.3892/ijmm.2019.4439
Yang, D.-S., Stavrides, P., Mohan, P. S., Kaushik, S., Kumar, A., Ohno, M., Schmidt, S. D., Wesson, D. W., Bandyopadhyay, U., Jiang, Y., Pawlik, M., Peterhoff, C. M., Yang, A. J., Wilson, D. A., St George-Hyslop, P., Westaway, D., Mathews, P. M., Levy, E., Cuervo, A. M., & Nixon, R. A. (2011). Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis. Autophagy, 7(7), 788–789. https://doi.org/10.4161/auto.7.7.15596
Zhang, B., Gu, G., Jiang, H., Guo, Y., Shen, X., Li, B., & Zhang, W. (2017). The value of whole-brain CT perfusion imaging and CT angiography using a 320-slice CT scanner in the diagnosis of MCI and AD patients. European Radiology, 27(11), 4756–4766. https://doi.org/10.1007/s00330-017-4865-1