A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease

• Published in: Cell death & disease Vol. 13; no. 1; p. 48
• Main Authors: Hu, Junkai, Lin, Stanley Li, Schachner, Melitta
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.01.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/51; 14/19; 38/35; 631/378/2612; 631/80/82; 64/60; Aging; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer Disease - prevention & control; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell adhesion & migration; Cell adhesion molecules; Cell Biology; Cell Culture; Circulatory system; Disease Models, Animal; DNA Topoisomerases, Type I - metabolism; Hippocampus; Hippocampus - metabolism; Hippocampus - pathology; Immunology; Intramolecular Oxidoreductases - metabolism; Leukocyte migration; Life Sciences; Macrophage migration inhibitory factor; Macrophage Migration-Inhibitory Factors - metabolism; Mice; Microglia; Microglia - metabolism; Neural cell adhesion molecule; Neural Cell Adhesion Molecule L1 - metabolism; Neurodegenerative diseases; Neurons - metabolism; Parabiosis; Peptide Fragments - metabolism; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Plaque, Amyloid - prevention & control; Senile plaques; Transforming Growth Factor beta1 - metabolism; β-Amyloid
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04348-6

Deposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.