Shino Magaki

Basement membrane components are integral to the physiologic function of cerebral microvessels. Immunotherapy (including by the use of lecanemab) in Alzheimer's disease patients may result in vascular complications identified by neuroimaging (ARIA-E and ARIA-H). This pilot study (on a relatively small number of human brain specimens) suggests one mechanism might be through the effects of lecanemab on a collagen component of said microvessel walls. It utilizes microvessels isolated from human brains (of Alzheimer's disease patients) and maintained in a viable state, to examine this mechanism using novel biochemical and molecular approaches. These yield preliminary evidence of how lecanemab may influence a specific component of the cerebral microvasculature and suggest other studies that may be used to address this important question.

In peripheral tissues, lipoprotein lipase (LPL) is secreted by parenchymal cells (adipocytes, myocytes) into the interstitial spaces, where it is captured by GPIHBP1 (a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells) and escorted to the luminal surface of capillaries. The LPL inside capillaries hydrolyzes glycerolipids in the plasma lipoproteins, releasing fatty acids for parenchymal cells. In the central nervous system, LPL is synthesized by multiple cell types [e.g., microglia, oligodendrocyte precursor cells (OPCs)] and secreted into the interstitium, but a binding site for the LPL has never been identified. By examining single nuclei RNA-seq databases of the human brain, we found that GPIHBP1 is expressed by oligodendrocytes but not by OPCs. This gene-expression profile (high in oligodendrocytes, low in OPCs) is also observed in genes for myelin structural proteins, fatty acid binding and transport proteins, and lipid biosynthetic enzymes. GPIHBP1 expression in oligodendrocytes was confirmed by in situ hybridization studies of human brain and by immunohistochemical staining. Of note, GPIHBP1 and LPL are colocalized on oligodendrocytes in the human brain. Our findings identify GPIHBP1 as a principal binding site for interstitial LPL in the human brain and suggest that GPIHBP1-bound LPL could hydrolyze interstitial lipids and thereby supply oligodendrocytes with fatty acid nutrients.

In peripheral tissues, an endothelial cell (EC) protein, GPIHBP1, captures lipoprotein lipase (LPL) from the interstitial spaces and transports it to the capillary lumen. LPL mediates the margination of triglyceride-rich (TG-rich) lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. TRL-derived fatty acids are used for fuel in oxidative tissues or stored in adipose tissue. In mice, GPIHBP1 is absent from capillary ECs of the brain (which uses glucose for fuel); consequently, LPL and TRL margination are absent in mouse brain capillaries. However, because fatty acids were reported to play signaling roles in the brain, we hypothesized that LPL-mediated TRL processing might occur within specialized vascular beds within the central nervous system. Here, we show that GPIHBP1 is expressed in capillary ECs of human and mouse choroid plexus (ChP) and that GPIHBP1 transports LPL (produced by adjacent ChP cells) to the capillary lumen. The LPL in ChP capillaries mediates both TRL margination and processing. Intracapillary LPL and TRL margination are absent in the ChP of Gpihbp1 ^–/– mice. GPIHBP1 expression, intracapillary LPL, and TRL margination were also observed in the median eminence and subfornical organ, circumventricular organs implicated in the regulation of food intake.

Elevated hexosamine biosynthesis fuels tumor growth by facilitating protein and lipid glycosylation. But which enzyme in this pathway is better to serve as an antitumor target remains unclear. Here, we revealed that targeting GFAT1, the rate-limiting enzyme in hexosamine synthesis, exhibits limited inhibitory effects on glioblastoma (GBM), the most lethal brain tumor. This outcome is due to the compensation of NAGK-mediated hexosamine salvage pathway. Unexpectedly, inhibiting PGM3, which controls the flux of both de novo hexosamine synthesis and salvage pathways, down-regulates the expression of other enzymes in this pathway and suppresses SREBP-1, a critical lipogenic transcription factor, effectively inhibiting GBM growth. Unexpectedly, SREBP-1 transcriptionally up-regulates the expression of hexosamine synthesis enzymes, while inhibition of these enzymes in turn down-regulates SREBP-1 activation via reducing N-glycosylation of its transporter, SCAP. Our study identified PGM3 as a promising target for treating GBM. Its inhibition disrupts the SREBP-1 activation-hexosamine synthesis positive feedback regulation to effectively eliminate GBM cells.

Neurotransmitters (NTs) mediate trans-synaptic signaling, and disturbances in their levels are linked to aging and brain disorders. Here, we ascribe an additional function for NTs in mediating intracellular protein aggregation by interaction with cytosolic protein fibrils. Cell-based seeding experiments revealed monoaminergic NTs as inhibitors of tau. Seeding is a disease-relevant mechanism involving catalysis by fibrils, leading to the aggregation of proteins in Alzheimer’s disease and other neurodegenerative diseases. Chemotyping small molecules with varied backbone structures revealed determinants of aggregation inhibitors and catalysts. Among those identified were monoaminergic NTs. Dose titrations revealed bimodal effects indicative of fibril disaggregation, with aggregation catalysis occurring at low ratios of NTs and inhibited seeding ensuing at higher concentrations. Bimodal effects by NTs extend from in vitro systems to dopaminergic neurons, suggesting that pharmacotherapies that modify intracellular NT levels could shape the neuronal protein aggregation environment.

Natural products are ligands and in vitro inhibitors of Alzheimer’s disease (AD) tau. Dihydromyricetin (DHM) bears chemical similarity to known natural product tau inhibitors. Despite having signature polyphenolic character, DHM is ostensibly hydrophobic owing to intermolecular hydrogen bonds that shield hydrophilic phenols. Our research shows DHM becomes ionized at near-neutral pH, allowing the formulation of salts with transformed solubility. The MicroED co-crystal structure with trolamine reveals DHM salts as metastable co-crystalline solids with unlocked hydrogen bonding and a thermodynamic bent to solubilize in water. All co-crystal formulations show better inhibitory activity against AD tau than the nonsalt form, with efficacies correlating to enhanced solubilities. In vitro and in vivo pharmacokinetic measures demonstrate that DHM co-crystals display enhanced absorption and distribution with altered rates of elimination, suggesting that co-crystal formulations could be strategically used to fine-tune delivery properties. These results underscore the role of structural chemistry in guiding the selection of solubilizing agents for chemical formulation. We propose DHM co-crystals are appropriate formulations for research as dietary supplements to promote healthy aging by combating protein misfolding, although central nervous system (CNS) delivery remains a major limitation. DHM may be a suitable backbone for medicinal chemistry and possible development of pharmaceuticals with enhanced CNS exposure.

Recent genetic studies have revealed that hemimegalencephaly (HME) is a multi‐system disorder associated with germline or mosaic variants within the PI3K‐mTOR‐GATOR1 signaling pathways. Patients with HME typically develop drug‐resistant epilepsy necessitating extensive evaluation, hemispherectomy, and long‐term management. We describe the role of a multidisciplinary team (MDT) for the diagnosis and management of recent patients with HME at UCLA who underwent hemispherectomy. Genetic evaluation identified nine patients with the following variants: NPRL3 x2 germline, PIK3CA mosaicism x4, MTOR mosaicism x1, AKT3 mosaicism x1, unknown x1. Each patient's MDT comprised 4–9 specialties. One child with a MTOR variant had persistent epilepsy after hemispherectomy, but addition of everolimus resulted in an 80% decrease in seizure frequency. Another child with hemihypertrophy and PIK3CA mosaic variant was offered targeted PIK3CA inhibitor treatment, alpelisib, for overgrowth. A third child with germline NPRL3 variant inherited from their unaffected mother resulted in a sibling being diagnosed with the variant who later developed seizures secondary to focal cortical dysplasia. The implementation of a MDT offers essential guidance for families affected by HME, encompassing prognostication, surveillance, and therapeutic strategies. Identifying the etiology of HME can facilitate the development of targeted treatments and enable timely genetic counseling.Plain Language Summary: Hemimegalencephaly (HME) is a complex brain disorder caused by genetic changes. It often leads to severe epilepsy that doesn't respond to standard treatments and frequently requires surgery. In this case series, nine patients with HME were identified and found to have genetic mutations in key growth‐regulating genes. A multidisciplinary team model was developed to facilitate patients' care. For example, one patient's seizures improved with surgery, another with a new targeted medication, and another received treatment for symptoms of overgrowth. This team approach provides comprehensive care for patients and can lead to efficient care coordination and implementation of novel therapies.