Knock-in of Human BACE1 Cleaves Murine APP and Reiterates Alzheimer-like PhenoTypes

Footnotes We thank Roemex and the College for Life Science and Medicine at the University of Aberdeen for their generous support. The authors declare no competing financial interests.Peer reviewedPublisher PD

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

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Effects of Liraglutide and Fenretinide treatments on the diabetic phenotype of neuronal human BACE1 knock-in mice

The authors would like to acknowledge University of Aberdeen PhD studentship to RD and Scottish Alzheimer’s Research UK Junior member research grant to RD to perform GLP-1 ELISA and Alzheimer’s Research UK grant to BP and MD (ARUK-PG2017B-11). We thank Dr Oliver Helk for advice concerning statistical analyses and Prof Gernot Riedel for kindly providing the PhenoTyper home cages and advice in behavioural studies.Peer reviewedPostprin

Effects of Liraglutide and Fenretinide treatments on the diabetic phenotype of neuronal human BACE1 knock-in mice

The authors would like to acknowledge University of Aberdeen PhD studentship to RD and Scottish Alzheimer’s Research UK Junior member research grant to RD to perform GLP-1 ELISA and Alzheimer’s Research UK grant to BP and MD (ARUK-PG2017B-11). We thank Dr Oliver Helk for advice concerning statistical analyses and Prof Gernot Riedel for kindly providing the PhenoTyper home cages and advice in behavioural studies.Peer reviewedPostprin

Cardiolipin synthesis in brown and beige fat mitochondria is essential for systemic energy homeostasis

Activation of energy expenditure in thermogenic fat is a promising strategy to improve metabolic health, yet the dynamic processes that evoke this response are poorly understood. Here we show that synthesis of the mitochondrial phospholipid cardiolipin is indispensable for stimulating and sustaining thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response through overexpression of cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency in thermogenic adipocytes diminishes inducible mitochondrial uncoupling and elicits a nuclear transcriptional response through endoplasmic reticulum stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake, which renders animals insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin has a powerful impact on organismal energy homeostasis through thermogenic fat bioenergetics