Yeojung Koh and al.

The authors demonstrate that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that catabolizes eicosanoids and other anti-inflammatory mediators, is enriched in blood-brain-barrier (BBB)-associated myeloid cells. It becomes markedly elevated in human and mouse models of Alzheimer’s disease (AD) and traumatic brain injury (TBI), as well as aging, another major risk factor for AD. Pathological increase in 15-PGDH correlates with pronounced oxidative stress, neuroinflammation, and neurodegeneration, alongside profound BBB structural degeneration characterized by astrocytic endfeet swelling and functional impairment. Pharmacologic inhibition or genetic reduction of 15-PGDH in AD and TBI models strikingly mitigates oxidative damage, suppresses neuroinflammation, and restores BBB integrity. Most notably, inhibiting 15-PGDH not only halts neurodegeneration but also preserves cognitive function at levels indistinguishable from healthy controls. Remarkably, these neuroprotective effects in AD are achieved without affecting amyloid pathology, underscoring a noncanonical mechanism for treating AD. In a murine microglia cell line exposed to amyloid beta oligomer, major protection was demonstrated by multiple anti-inflammatory substrates that 15-PGDH degrades.

Priya Prakash and al.

Microglial phagocytosis genes have been linked to increased risk for Alzheimer’s disease (AD), but the mechanisms translating genetic association to cellular dysfunction remain unknown. Here, the authors showed that microglia formed lipid droplets (LDs) upon amyloid-β (Aβ) exposure and that LD loads increased with proximity to amyloid plaques in brains from individuals with AD and the 5xFAD mouse model. LD-laden microglia exhibited defects in Aβ phagocytosis, and unbiased lipidomic analyses identified a parallel decrease in free fatty acids (FFAs) and increase in triacylglycerols (TGs) as the key metabolic transition underlying LD formation. Diacylglycerol O-acyltransferase 2 (DGAT2), a key enzyme that converts FFAs to TGs—promoted microglial LD formation and was increased in mouse 5xFAD and human AD brains. Pharmacologically targeting DGAT2 improved microglial uptake of Aβ and reduced plaque load and neuronal damage in 5xFAD mice.

Sara I. Graves and al.

The authors previously demonstrated that targeted elimination of senescent cells prevents neurodegenerative disease in tau (MAPTP301S;PS19) mutant mice. Here, they show that genetic ablation of the senescence mediator p16Ink4a is sufficient to attenuate senescence signatures in PS19 mice. Disease phenotypes—including neuroinflammation, phosphorylated tau, neurodegeneration, and cognitive impairment—were blunted in the absence of p16Ink4a. Additionally, PS19 mouse brains were found to display p16Ink4-dependent neurovascular alterations such as vessel dilation, increased vessel density, deregulated endothelial cell extracellular matrix, and astrocytic endfoot depolarization. Finally, p16Ink4a deletion in endothelial cells and microglia alone attenuates many of the same phenotypes.

Jing Liu and al.

The authors report that amyloid-beta (Aβ) induced a decrease in TMEM119 expression in microglia, and TMEM119 deficiency increased Alzheimer’s disease (AD) progression in the 5×FAD mouse model. TMEM119 bound to Aβ oligomers and recruited low-density lipoprotein receptor 1 (LRP1), which in turn degraded TMEM119 itself. Overexpression of TMEM119 in microglia enhanced their phagocytic activity and alleviated cognitive deficits in 5xFAD mice. Administration of the small molecules Kartogenin and SRI-011381, which enhanced TMEM119 expression, substantially promoted Aβ clearance and improved cognitive function in AD mice, even during the mid-stage of the disease.

Anna C. Geraghty and al.

The authors show in mouse models that chimeric antigen receptor (CAR) T cell therapy for both central nervous system (CNS) and non-CNS cancers impairs cognitive function and induce a persistent CNS immune response characterized by white matter microglial reactivity, microglial chemokine expression, and elevated cerebrospinal fluid (CSF) cytokines and chemokines. Consequently, oligodendroglial homeostasis and hippocampal neurogenesis are disrupted. Single-nucleus sequencing studies of human frontal lobe from patients with or without previous CAR T cell therapy for brainstem tumors confirmed reactive states of microglia and oligodendrocytes following treatment. In mice, transient microglial depletion or CCR3 chemokine receptor blockade rescue oligodendroglial deficits and cognitive performance in a behavioral test of attention and short-term memory function following CAR T cell therapy.