Chloe Todd

Introduction: Alzheimer’s disease (AD) is the leading cause of dementia, projected to affect 150 million people worldwide by 2050.¹ Current treatment focuses on improving patients’ symptoms; pharmacological therapy does not yet address disease pathology.² AD pathogenesis begins with aggregation of β-amyloid (Aβ) protein in the brain.¹ Amyloid precursor protein (APP) is cleaved into Aβ by β- and γ-secretase, composed of presenilins (PS1/2).^1,3 Aβ deposition promotes phosphorylation of tau, leading to neuronal death and cognitive impairment.³ Recent emphasis has been placed on neuroinflammation, which exacerbates Aβ plaque formation.³ Long-term nonsteroidal anti-inflammatory drug (NSAID) use has been associated with reduced risk of AD, suggesting a pathological mechanism involving COX-2, but this is an impractical therapy.³ Further knowledge about the downstream actions of COX-2 prostaglandins could lead to the development of a specific pharmacological target preventing or reversing Aβ deposition. Methods: APP/PS1 AD model mice were crossbred to overexpress COX-2, and researchers measured cognitive function, Aβ aggregation, and expression of downstream effectors of COX-2.⁴ Researchers investigated the mechanistic effect of PGE₂ on bioenergetics in human-derived macrophages and microglia using treatment with PGE₂ and inhibitors to its receptor EP2.⁵ Another experiment used 4 groups of mice: wildtype, one-hit AD genetic, one-hit inflammatory environmental with lipopolysaccharide (LPS), and two-hit genetic and environmental.⁶ Half of each group was treated with an EP2 antagonist to measure effects on neuroinflammation.⁶ Results: COX-2 overexpression resulted in increased Aβ plaques in the APP/PS1 AD model mice brains, as well as decreased cognitive ability, confirming necessity in AD pathogenesis.⁴ COX-2 inhibition by NS398 prevented Aβ plaque formation and reduced synthesis of PGE₂, corresponding to decreased TNF-α and PS1/2, indicating that PGE₂ has a stronger influence than other prostaglandins on AD neuroinflammation.⁴ PGE₂ treatment to macrophages resulted in depression of glycolysis, oxidative respiration, and glucose utilization, all of which were reversed with EP2 inhibitors.⁵ Moreover, these EP2 inhibitors and EP2 gene knockdown were able to improve cognition in aged mice.⁵ Administration of EP2 antagonist did decrease levels of TNF-α and other pro-inflammatory factors in the two-hit AD model mice mimicking genetic and environmental predisposition, but no effects were seen in the one-hit groups.⁶ Conclusions: PGE₂ and its receptor EP2 are crucial to AD pathogenesis through the manipulation of cellular bioenergetics and upregulation of TNF-α, which in turn upregulates β-secretase and PS1/2 to promote Aβ deposition.^4,6-8 Inhibition of EP2 shows promise as a target to prevent and even reverse early AD-related cognitive decline.^5,6

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2. Knopman DS, Amieva H, Petersen RC, et al. Alzheimer disease. Nat Rev Dis Primers. May 13 2021;7(1):33. doi:10.1038/s41572-021-00269-y
3. Biringer RG. The Role of Eicosanoids in Alzheimer’s Disease. Int J Environ Res Public Health. Jul 18 2019;16(14)doi:10.3390/ijerph16142560
4. Guan PP, Liang YY, Cao LL, Yu X, Wang P. Cyclooxygenase-2 Induced the beta-Amyloid Protein Deposition and Neuronal Apoptosis Via Upregulating the Synthesis of Prostaglandin E2 and 15-Deoxy-Delta(12,14)-prostaglandin J2. Neurotherapeutics. Oct 2019;16(4):1255-1268. doi:10.1007/s13311-019-00770-z
5. Minhas PS, Latif-Hernandez A, McReynolds MR, et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature. Feb 2021;590(7844):122-128. doi:10.1038/s41586-020-03160-0
6. Banik A, Amaradhi R, Lee D, et al. Prostaglandin EP2 receptor antagonist ameliorates neuroinflammation in a two-hit mouse model of Alzheimer’s disease. J Neuroinflammation. Nov 20 2021;18(1):273. doi:10.1186/s12974-021-02297-7
7. Zheng SQ, Gong ZY, Lu CD, Wang P. Prostaglandin I2 is responsible for ameliorating prostaglandin E2 stress in stimulating the expression of tumor necrosis factor alpha in a beta-amyloid protein -dependent mechanism. Oncotarget. Nov 28 2017;8(61):102801-102819. doi:10.18632/oncotarget.18462
8. Bitto A, Giuliani D, Pallio G, et al. Effects of COX1-2/5-LOX blockade in Alzheimer transgenic 3xTg-AD mice. Inflamm Res. May 2017;66(5):389-398. doi:10.1007/s00011-017-1022-x