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    • This suggestion was confirmed by immunohistochemical studies

    2023-08-17

    This suggestion was confirmed by immunohistochemical studies in which the immunoreactivity of the enzyme was actually higher at the earlier rather than at the advanced stages of the disease. Importantly, a later study showed that the biochemical signature of 12/15LO enzymatic activation (i.e., 12-HETE and 15-HETE) was significantly increased also in cerebrospinal fluid of individuals with a clinical diagnosis of AD as well as mild cognitive impairments compared to aged-matched normal individuals [32]. Because mild cognitive impairment is believed to be a prodromal stage to AD in some patients, this finding has significant implications for AD biomarker development and early diagnostic screening. More recently, lipidomic analyses using PFI 3 tissues and plasma obtained from transgenic mice expressing mutated human APP and tau protein (Tg2576×JNPL3) (APP/tau mice) at 4 (pre-symptomatic phase), 10 (early symptomatic), and 15 months (late symptomatic) revealed increased levels of 12/15LO metabolic products during the early phase of their phenotype development [33].
    12/15LO and AD pathology In a series of in vitro studies using neuronal cells stably expressing human APP containing the Swedish familial AD mutation, a widely used cellular AD model, two structurally distinct and selective 12/15LO inhibitors, PD146176 and CDC, were found to dose-dependently reduce Aβ formation without affecting total APP levels [34]. Interestingly, these studies revealed for the first time that 12/15LO inhibition reduced BACE-1 levels and its enzymatic products, but not those of the α-secretase pathway [35]. Compared to wild type mice, transgenic mice carrying the same APP Swedish mutation (known as Tg2576 mice, one of the most common models of AD-like amyloidosis) had significant elevations in the brain levels and activity of 12/15LO. Strikingly, when Tg2576 mice were crossed with 12/15LO knockout mice, the newly generated animals had a significant reduction in levels and deposition of Aβ peptides. In the Tg2576 animals lacking 12/15LO, BACE-1 levels were reduced compared to Tg2576 animals with 12/15LO intact, mirroring the in vitro data [34]. By contrast, Tg2576 mice stably overexpressing 12/15LO were found to have a significant increase in Aβ peptide levels and deposition [36]. In vivo and in vitro studies showed that the effect of this enzymatic pathway on amyloidosis was indeed mediated by modulation of APP processing via the transcriptional regulation of BACE-1 mRNA levels, which involved the activation of the transcription factor Sp1 [36]. In sum, these data show that this enzymatic pathway directly influences Aβ formation via a BACE-1 dependent mechanism, and that its pharmacological inhibition could represent a novel therapeutic target for AD. These findings were further supported by pharmacological studies in which Tg2576 mice were administered a selective inhibitor of 12/15LO (PD 146176) for 6 weeks. At the end of the study, mice receiving the drug had a significant reduction (>70%) of 12/15LO enzyme activity, and this was associated with a significant reduction in amyloid plaques, a decrease in brain Aβ levels via downregulation of BACE-1 and APP cleavage, and reduced levels of transcriptional factor Sp1 [36]. Interestingly, along with the effect on Aβ, endogenous tau phosphorylation also appeared to be modified by 12/15LO modulation because Tg2576 mice overexpressing 12/15LO had increased levels of phosphorylated tau but no changes in total tau levels [37]. Intriguingly, 12/15LO overexpression was associated with phosphorylation of both early- and advanced-stage tau epitopes, suggesting its involvement in the entire range of AD-associated tauopathy. However, although Tg2576 animals develop Aβ plaques, they do not develop neurofibrillary tangles. To see how advanced tau neuropathology was modified, in a recent paper we evaluated the effect of pharmacological inhibition of 12/15LO in the triple transgenic mice (3xTg) which develop both Aβ plaques and neurofibrillary tau tangles [38]. Compared to controls, 3xTg mice treated with PD146176 (a specific 12/15LO inhibitor) had significant reductions in Aβ peptide levels, amyloid plaque burden, tau phosphorylation, and insoluble tau deposition (i.e., neurofibrillary tangles). As with work in Tg2576 animals, changes in Aβ were associated with changes in BACE-1, whereas the phosphorylation of tau was linked to modulation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) activity [39]. In vitro data in that same paper revealed that 12/15LO modulation of tau occurs independently of Aβ because pharmacological suppression of Aβ formation by selective γ-secretase inhibition was not sufficient to prevent the 12/15LO-mediated increase in tau phosphorylation. This finding is particularly important because it suggests that 12/15LO independently modulates both Aβ production and tau phosphorylation, and this would implicate that 12/15LO inhibition has potential not only in amyloidotic diseases such as AD but also in other tauopathies.