Consequences of Amyloid-β Deficiency for the Liver

The hepatic content of amyloid beta (A beta) decreases drastically in human and rodent cirrhosis highlighting the importance of understanding the consequences of A beta deficiency in the liver. This is especially relevant in view of recent advances in anti-A beta therapies for Alzheimer's disease (AD). Here, it is shown that partial hepatic loss of A beta in transgenic AD mice immunized with A beta antibody 3D6 and its absence in amyloid precursor protein (APP) knockout mice (APP-KO), as well as in human liver spheroids with APP knockdown upregulates classical hallmarks of fibrosis, smooth muscle alpha-actin, and collagen type I. A beta absence in APP-KO and deficiency in immunized mice lead to strong activation of transforming growth factor-beta (TGF beta), alpha secretases, NOTCH pathway, inflammation, decreased permeability of liver sinusoids, and epithelial-mesenchymal transition. Inversely, increased systemic and intrahepatic levels of A beta 42 in transgenic AD mice and neprilysin inhibitor LBQ657-treated wild-type mice protect the liver against carbon tetrachloride (CCl4)-induced injury. Transcriptomic analysis of CCl4-treated transgenic AD mouse livers uncovers the regulatory effects of A beta 42 on mitochondrial function, lipid metabolism, and its onco-suppressive effects accompanied by reduced synthesis of extracellular matrix proteins. Combined, these data reveal A beta as an indispensable regulator of cell-cell interactions in healthy liver and a powerful protector against liver fibrosis.