A fragment of cell adhesion molecule L1 reduces amyloid-\u03b2 plaques in a mouse model of Alzheimer\u2019s disease

Junkai Hu,Stanley Li Lin,Melitta Schachner

doi:10.1038/s41419-021-04348-6

Abstract

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.

Highlights

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease and is the most common cause of dementia among older adults [1, 2]
Levels of L1-70 and full-length L1 are decreased in the hippocampus of aged APPswe mice showing increased deposition of amyloid β-protein (Aβ) L1 is increased in the cerebrospinal fluid of AD patients [19], attenuates the deposition of Aβ in the hippocampus of aged APPswe mice [20], and is cleaved into a 70 kDa fragment (L1-70) (Supplemental Fig. 1), that enters mitochondria and the nucleus [25, 26]
In order to further understand the in situ expression of L1-70 and L1, and its relationship with Aβ deposition in the hippocampus, brains from 18-month-old wild-type and 18-month-old APPswe were fixed with formalin for paraffin sections, and immunofluorescence staining was carried out with anti-L1 cytoplasmic domain

Summary

Introduction

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease and is the most common cause of dementia among older adults [1, 2]. Other histopathological features of AD include nerve fiber tangles caused by hyperphosphorylation of tau protein within neurons, diffuse inflammatory necrotic foci, and loss of neurons [4]. The amyloid cascade and tau hyperphosphorylation hypotheses were formed in the 1980s based on these AD pathological characteristics [5,6,7,8]. L1 binds to Aβ and reduces Alzheimer’s disease pathology in mice when full-length L1encoding adeno-associated virus is injected into the hippocampus and occipital cortex of AD mice expressing a mutant APP gene [20]. L1 ameliorates some aspects of Aβ1-42 pathology in parallel with reducing protein kinase D1 (PKD1) function [21]. We hypothesized that L1 and, in particular, L1-70 could attenuate AD pathogenesis

Methods

Results

Conclusion