15-PGDH inhibition preserves blood–brain barrier integrity and cognition

One of the hallmark features of Alzheimer’s disease (AD) and traumatic brain injury (TBI) is the reduction of blood–brain barrier (BBB) integrity (1). Both AD and TBI, like many other neuroinflammatory and neurodegenerative diseases, still lack effective treatments, and efforts to preserve BBB integrity have been hampered by a lack of applicable therapeutic targets. The recent study of Koh et al. reveals that the protein 15-hydroxyprostaglandin dehydrogenase (15-PGDH) can be regarded as a novel therapeutic target for AD and TBI (2). In particular, they showed that transcript levels of 15-PGDH were increased during aging as well as in people with AD or TBI, with specific enrichment of 15-PGDH expression in myeloid cells associated with the BBB. Importantly, pharmacological and genetic inhibition of 15-PGDH in mouse models of AD and TBI preserved BBB integrity, reduced neuroinflammation and oxidative stress in BBB-associated myeloid cells, and improved cognition. As the effects occurred independently of reduction in amyloid-beta (Aβ) pathology, these findings suggest that 15-PGDH inhibition could potentially provide an additional noncanonical approach to existing Aβ-targeting treatments.

15-PDGH Inhibition: Mode of Action?

The enzyme 15-PGDH is primarily recognized for its role in tissue regeneration in peripheral organs such as the bone marrow, skeletal muscle, colon, and liver (3, 4). Koh et al. investigated the role of 15-PGDH within the central nervous system and revealed that inhibition of 15-PGDH improves BBB integrity, via decreased reactive oxygen species (ROS) production in BBB-associated myeloid cells, and a reduction of astrocytic end feet swelling. Furthermore, they demonstrate that inhibition of 15-PGDH effectively reduces astrocyte reactivity in the 5xFAD mouse model, without significantly affecting microglial activation, highlighting the potential contributary role of astrocytes in the underlying mechanism of action of 15-PGDH (Fig. 1). However, the interplay between myeloid cells, neuroinflammation, and vascular dysfunction in AD remains mechanistically unclear. Untangling this warrants further investigation to not only better understand the biology behind this interplay but also to explore how regulating astrocytes, alongside the BBB-associated myeloid cells, could be leveraged as a potential therapeutic target in AD.

Fig. 1.

Targeting 15-PGDH preserves BBB function and prevents neurodegeneration. Increased levels of 15-PGDH transcripts are found in the human and mouse brain during aging, AD, and TBI. In mice, 15-PGDH expression is predominantly found in myeloid cells like microglia and perivascular macrophages (PVMs). This leads to pronounced ROS production (oxidative stress), neuroinflammation, and neurodegeneration. Genetical or pharmacological inhibition of 15-PGDH leads to a reduction of astrocytic end feet swelling and a decrease of immunoglobulin (IgG) leakage into the brain parenchyma in both AD and TBI mouse models. In turn, BBB integrity is preserved, which coincides with a decrease of ROS production by microglia and PVMs. Additionally, 15-PGDH inhibition reduces the expression of glial fibrillary acidic protein (GFAP) in astrocytes and leads to an enhanced cognitive performance in vivo, independently of a reduction in Aβ pathology. This figure was created using Biorender.

Besides the observed effects on affecting the BBB, 15-PDGH is known to play a central role in a broader regulatory cascade. Indeed, 15-PGDH is an oxidoreductase that oxidizes 15(S)-hydroxyl groups on various bioactive lipid mediators (LMs), primarily prostaglandins such as prostaglandin E₂ (PGE₂), prostaglandin F_2α (PGF_2α), and to a lesser extent prostaglandin D₂ (PGD₂) (5). Such prostanoids are derived from polyunsaturated fatty acids like arachidonic acid, and together with LMs derived from eicosapentaenoic acid and docosahexaenoic acid, they play a central role in the regulation of both inflammation and resolution responses (6). An outstanding question therefore remains whether the observed effects of 15-PGDH inhibition are, in part, mediated by specific LMs. Indeed, previous literature suggests that LMs can modulate ROS production (7) and prevent inflammation-induced BBB impairment (8). To address this fundamental question, Koh et al. showed that Aβ-induced toxic ROS production in myeloid cells could be suppressed by PGE₂ as well as other LMs that are substrates for 15-PGDH, suggesting that such LMs drive the observed protective effects. The current paper has minor but important limitations noted by the authors that includes providing direct evidence for modified LM levels upon 15-PDGH inhibition using a lipidomics approach. In combination with providing spatial LM information by using novel imaging techniques for PGE₂ (9) as well as other LMs, it will be possible to define the cellular producers in a pathological setting. In turn, this will aid in the understanding of the underlying mechanism of action upon 15-PGDH inhibition.

The recent study of Koh et al. reveals that the protein 15-hydroxyprostaglandin dehydrogenase (15-PGDH) can be regarded as a novel therapeutic target for AD and TBI (2).

Another layer of complexity is that LMs like PGE₂ can interact with multiple receptors, some with opposing actions (10). So besides LM profiling, underlying regulatory signaling pathways should be investigated. For instance, PGE₂ can trigger neutrophil recruitment, promoting Th17 cell expansion and blocking Treg differentiation (11). Conversely, PGE₂ can also inhibit Th1 induction and shift macrophages toward a more anti-inflammatory phenotype (11). As 15-PGDH acts as a key regulator of sustained PGE₂ levels, the study of Koh et al. contributes to our general understanding of targeting lipid-related pathways in AD that might affect the neuroinflammatory and neurodegenerative aspects of the disease.

Interestingly, there is a strong connection between lipids and AD, as various AD risk genes are related to lipid metabolism such as ApoE, TREM2, ABCA7, and PLCg2 (12). Emerging evidence also suggests an important role for altered LM production and local signaling pathways during AD (13), and these alterations correlate with cognitive impairment (14). Thus, modulating lipid metabolism represents a promising strategy to counteract neuroinflammation, neurodegeneration, and cognitive decline in AD. However, supplementing with LMs is challenging due to their short half-life, which makes targeting lipid-related enzymes, like 15-PGDH, a more promising approach. Pharmaceutical companies have indeed developed small-molecule inhibitors targeting 15-PGDH as a therapeutic approach to locally elevate PGE₂ levels, thereby promoting tissue regeneration and repair in various organs (3, 15). The findings of Koh et al. reveal the potential for repurposing 15-PGDH inhibitors to treat neurodegenerative diseases associated with BBB impairment and altered lipid metabolism, such as AD.

Clinical Implications of 15-PGDH Inhibition in Neurodegenerative Diseases.

Despite the development of promising strategies to target lipid metabolism, developing effective treatments for AD has been challenging. These challenges arise, not only from the inherent complexity of the disease but also from limitations concerning the translatability of the models in use, as well as skepticism surrounding the therapeutic approaches based on the Aβ hypothesis. Koh et al. propose a noncanonical mechanism of action that improves cognition in the 5xFAD animal model, and although these results have not yet been validated in human models, the upregulation of 15-PGDH in people with AD, TBI, and aging offers great hope for translating these findings to the clinic.

The noncanonical approach to AD therapy opens up promising new avenues for intervention, especially given the observed indirect effects of LMs. Previous studies have demonstrated positive effects of LMs on AD pathology (16, 17); however, these effects may vary depending on the specific mouse model in use. Therefore, it will also be of interest to test whether modification of 15-PGDH levels is additionally protective in tau-based models of AD and models that better resemble the sporadic form of AD, where multiple pathophysiological and environmental factors are at play. Moreover, exploring combination therapies that target Aβ pathology together with 15-PGDH inhibition may offer insights into the potential synergistic effects on disease progression. Such approaches could help determine whether 15-PGDH inhibition represents a novel strategy for the treatment and prevention of AD, addressing the pressing need for more effective therapies.

As discussed above, the authors attribute the mode of action of 15-PGDH inhibition to limiting oxidative stress and preserving BBB integrity. In AD, oxidative stress and BBB dysfunction are thought to occur early in disease progression (1). It remains unclear yet, whether administering this inhibitor early, before cognitive impairment becomes evident, could help preserve cognitive function and halt disease progression. Therefore, to evaluate the therapeutic potential of 15-PGDH and its putative clinical application, it is crucial to understand the biosafety profile of targeting 15-PGDH, particularly the timing, duration, and potential off-target effects, as well as its contribution to other neurodegenerative diseases associated with BBB impairment and neuroinflammation.

For instance, while increased 15-PGDH may contribute negatively to disease pathology in AD and TBI, its role in other chronic neuroinflammatory diseases associated with BBB impairment might be fundamentally different, potentially even protective. For example, in a well-established animal model for multiple sclerosis, it was shown that 15-PGDH levels were decreased (18). Together, these findings further underscore the necessity to systematically characterize the precise effects and underlying mechanism of 15-PGDH and its inhibition across different neurological paradigms in order to identify specific treatment strategies to combat BBB and lipid-associated neurodegenerative diseases.