Revisiting APP secretases: an overview on the holistic effects of retinoic acid receptor stimulation in APP processing

• Published in: Cellular and molecular life sciences : CMLS Vol. 79; no. 2; p. 101
• Main Authors: Vitória, José J. M., Trigo, Diogo, da Cruz e Silva, Odete A. B.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01-02-2022; Springer Nature B.V
• Subjects: ADAM10 Protein - metabolism; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Amyloid Precursor Protein Secretases - metabolism; Amyloidogenesis; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Brain; Brain - metabolism; Brain - pathology; Cell Biology; Cleavage; Dementia disorders; Humans; Life Sciences; Neurodegenerative diseases; Neurotoxicity; Peptides; Phosphorylation; Proteolysis; Receptors; Receptors, Retinoic Acid - metabolism; Retinoic acid; Retinoic acid receptors; Review; Secretase; Signal transduction; Signaling; Therapeutic targets; Toxicity; β-Amyloid; β-Site APP-cleaving enzyme 1; APP; Alzheimer’s disease; Neuroregeneration; APP-secretases; RAR stimulation
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-021-04090-4

Alzheimer's disease (AD) is the leading cause of dementia worldwide and is characterized by the accumulation of the β-amyloid peptide (Aβ) in the brain, along with profound alterations in phosphorylation-related events and regulatory pathways. The production of the neurotoxic Aβ peptide via amyloid precursor protein (APP) proteolysis is a crucial step in AD development. APP is highly expressed in the brain and is complexly metabolized by a series of sequential secretases, commonly denoted the α-, β-, and γ-cleavages. The toxicity of resulting fragments is a direct consequence of the first cleaving event. β-secretase (BACE1) induces amyloidogenic cleavages, while α-secretases (ADAM10 and ADAM17) result in less pathological peptides. Hence this first cleavage event is a prime therapeutic target for preventing or reverting initial biochemical events involved in AD. The subsequent cleavage by γ-secretase has a reduced impact on Aβ formation but affects the peptides’ aggregating capacity. An array of therapeutic strategies are being explored, among them targeting Retinoic Acid (RA) signalling, which has long been associated with neuronal health. Additionally, several studies have described altered RA levels in AD patients, reinforcing RA Receptor (RAR) signalling as a promising therapeutic strategy. In this review we provide a holistic approach focussing on the effects of isoform-specific RAR modulation with respect to APP secretases and discuss its advantages and drawbacks in subcellular AD related events.