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Pericytes are vascular mural cells that support the microvasculature; their dysfunction contributes to diabetic retinopathy and has been linked to obesity in humans. To explore the role of pericyte insulin signalling on systemic metabolism we utilised male mice from our previously described PIR -/- (PIRKO) mouse line which has insulin receptor (Insr) knockout in PDGFRβ-expressing cells. These animals exhibit systemic insulin resistance from as early as 8-weeks of age, despite no change in body weight or activity level, and show altered body composition and hepatosteatosis. When challenged with high fat diet, PIR -/- remain insulin resistant but are protected from weight gain with reduced adipose tissue expansion across all depots and altered adipose morphology. Exhibiting parallels with the metabolically-obese-normal-weight (MONW) human phenotype, the PIR -/- line underlines the importance of pericyte biology in the development of both diabetes and obesity and establishes the angiopoietin (Ang)/Tie signalling pathway as a focus for future research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Niemann-Pick disease type C and Alzheimer's disease are distinct neurodegenerative disorders that share the presence of neurofibrillary tangle pathology. In this multicentre study, we measured plasma phosphorylated-tau217 in controls ( n = 60), Niemann-Pick disease type C ( n = 71) and Alzheimer's disease ( n = 30 positive for amyloid and negative for tau in CSF [A + T - ] and n = 30 positive for both [A + T + ]). Annual Severity Increment Score and Lysotracker measurements were evaluated in the Niemann-Pick disease type C group to estimate the rate of progression and lysosomal enlargement, respectively. In the cross-sectional analysis, plasma phosphorylated-tau217 was increased in Niemann-Pick disease type C compared with controls (2.52 ± 1.93 versus 1.02 ± 0.34 pg/mL, respectively, P < 0.001) and inversely correlated with age at disease onset ( R = -0.54, P < 0.001). In the longitudinal analysis, plasma phosphorylated-tau217 was associated with disease progression determined by Annual Severity Increment Score ( R = 0.48, P < 0.001) and lysosomal enlargement ( R = 0.26, P = 0.004). We found no differences between A + T - Alzheimer's disease and Niemann-Pick disease type C (2.67 ± 1.18 versus 2.52 ± 1. 93 pg/mL, P = 0.31); however, A + T + Alzheimer's disease had significantly higher levels than Niemann-Pick disease type C (3.26 ± 1.36 versus 2.52 ± 1.93 pg/mL, P = 0.001). Our findings suggest that plasma p-tau217 can increase in brain disorders with isolated tau pathology. Plasma p-tau217 associations with disease progression and severity make it a potential marker in Niemann-Pick disease type C., Competing Interests: K.B. has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; and has given lectures, produced educational materials and participated in educational programmes for AC Immune, Biogen, BioArctic, Celdara Medical, Eisai and Roche Diagnostics. K.B. is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. B.-E.K. has served as a consultant for Biogen. The other authors declare no competing interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1 . We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1 . Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1 . We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1 . These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function-yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.