Low-grade peripheral inflammation affects brain pathology in the AppNL-G-Fmouse model of Alzheimer\u2019s disease

Junhua Xie,Nina Gorlé,Eef Parthoens,Elien Van Wonterghem,Evelien Van Hamme,Griet Van Imschoot,Saskia Lippens,Caroline Van Cauwenberghe,Charysse Vandendriessche,Roosmarijn E Vandenbroucke,Lien Van Hoecke

doi:10.1186/s40478-021-01253-z

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the accumulation of amyloid β (Aβ) and neurofibrillary tangles. The last decade, it became increasingly clear that neuroinflammation plays a key role in both the initiation and progression of AD. Moreover, also the presence of peripheral inflammation has been extensively documented. However, it is still ambiguous whether this observed inflammation is cause or consequence of AD pathogenesis. Recently, this has been studied using amyloid precursor protein (APP) overexpression mouse models of AD. However, the findings might be confounded by APP-overexpression artifacts. Here, we investigated the effect of low-grade peripheral inflammation in the APP knock-in (AppNL-G-F) mouse model. This revealed that low-grade peripheral inflammation affects (1) microglia characteristics, (2) blood-cerebrospinal fluid barrier integrity, (3) peripheral immune cell infiltration and (4) Aβ deposition in the brain. Next, we identified mechanisms that might cause this effect on AD pathology, more precisely Aβ efflux, persistent microglial activation and insufficient Aβ clearance, neuronal dysfunction and promotion of Aβ aggregation. Our results further strengthen the believe that even low-grade peripheral inflammation has detrimental effects on AD progression and may further reinforce the idea to modulate peripheral inflammation as a therapeutic strategy for AD.

Highlights

Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder that is characterized by the progressive and disabling deficits in cognitive functions including reasoning, attention, judgment, comprehension, memory and language
We checked the expression of leukocyte trafficking molecules in the brain during peripheral inflammation and we show that exposure to LPS significantly increases the expression levels of integrin ligand (Icam1) and chemokines (Ccl2 and Cxcl10) in the hippocampus and/or choroid plexus (CP) of WT and AppNL-G-F mice 24 h after the second LPS injection
The levels of amyloid β (Aβ) peptides are not significantly changed 24 h after LPS stimulation (Fig. 5d). These results suggest that low-grade peripheral inflammation affects Aβ deposition in AppNL-G-F mice, which may be the result of aberrant Aβ clearance from the brain

Summary

Introduction

Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder that is characterized by the progressive and disabling deficits in cognitive functions including reasoning, attention, judgment, comprehension, memory and language. AD is the most common form of dementia and may contribute to 60–70% of cases [1]. Nearly 50 million people have AD or related dementia, and this number will multiply in the decades [1]. The speed of disease progression is subjective to individual variability, but patients are estimated to live from a few up to 20 years after their diagnosis [1]. To dramatically affecting the life quality and expectancy of patients, the disease takes its toll on our healthcare system and is becoming one of the most economically taxing diseases in developed countries. Only symptomatic medication that is effective for some AD patients is available, but no cure nor treatment to reverse or even halt disease progression exists

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