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Metabolic changes that correlate to cognitive changes are well-known in Alzheimer's disease (AD). Metabolism is often linked to functional changes in proteins by post-translational modifications. The importance of the regulation of transcription by acetylation is well documented. Advanced mass spectrometry reveals hundreds of acetylated proteins in multiple tissues, but the acetylome of human brain, its functional significance, and the changes with disease are unknown. Filling this gap is critical for understanding the pathophysiology and development of therapies. To fill this gap, we assessed the human brain acetylome in human brain and its changes with AD. More than 5% of the 4,442 proteins from the human brain global proteome were acetylated. Acetylated proteins were primarily found in the cytosol (148), mitochondria (100), nucleus (91), and plasma membrane (58). The comparison of the brain acetylome in controls to that of patients with AD revealed striking and selective differences in terms of its abundances of acetylated peptides/sites. Acetylation of 18 mitochondrial proteins decreased, while acetylation of two cytosolic proteins, tau and GFAP, increased. Our experiments demonstrate that acetylation at some specific lysine sites alters enzyme function. The results indicate that general activation of de-acetylases (i.e., sirtuins) is not an appropriate therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

Mitochondria and releasable endoplasmic reticulum (ER) calcium modulate neuronal calcium signaling, and both change in Alzheimer's disease (AD). The releasable calcium stores in the ER are exaggerated in fibroblasts from AD patients and in multiple models of AD. The activity of the alpha‐ketoglutarate dehydrogenase complex (KGDHC), a key mitochondrial enzyme complex, is diminished in brains from AD patients, and can be plausibly linked to plaques and tangles. Our previous studies in cell lines and mouse neurons demonstrate that reductions in KGDHC increase the ER releasable calcium stores. The goal of these studies was to test whether the relationship was true in human iPSC‐derived neurons. Inhibition of KGDHC for one or 24 hr increased the ER releasable calcium store in human neurons by 69% and 144%, respectively. The effect was mitochondrial enzyme specific because inhibiting the pyruvate dehydrogenase complex, another key mitochondrial enzyme complex, diminished the ER releasable calcium stores. The link of KGDHC to ER releasable calcium stores was cell type specific as the interaction was not present in iPSC or neural stem cells. Thus, these studies in human neurons verify a link between KGDHC and releasable ER calcium stores, and support the use of human neurons to examine mechanisms and potential therapies for AD. [ABSTRACT FROM AUTHOR]

Innate immunity protein interferon induced transmembrane protein 3 (IFITM3) is a transmembrane protein that has a wide array of functions, including in viral infections, Alzheimer's Disease (AD), and cancer. As an interferon stimulated gene (ISG), IFITM3's expression is upregulated by type-I, II, and III interferons. Moreover, the antiviral activity of IFITM3 is modulated by post-translational modifications. IFITM3 functions in innate immunity to disrupt viral fusion and entry to the plasma membrane as well as prevent viral escape from endosomes. As a γ-secretase modulatory protein, IFITM3 distinctly modulates the processing of amyloid precursor protein (APP) to generate amyloid beta peptides (Aβ) and Notch1 cleavages. Increased IFITM3 expression, which can result from aging, cytokine activation, inflammation, and infection, can lead to an upregulation of γ-secretase for Aβ production that causes a risk of AD. Therefore, the prevention of IFITM3 upregulation has potential in the development of novel therapies for the treatment of AD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yue-Ming Li reports a relationship with Memorial Sloan Kettering Cancer Center that includes: funding grants. If there are other authors, they 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 Author(s). Published by Elsevier Inc. All rights reserved.)