The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer's disease

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) accumulation, tau pathology and neuroinflammation. Recently, there has been considerable interest in the role of neuroinflammation in directly contributing to the progression of AD. Studies in mice and humans have identified a role for microglial cells, the resident innate immune cells of the central nervous system, in AD. Activated microglia are a key hallmark of the disease and the secretion of proinflammatory cytokines by microglia may result in a positive feedback loop between neurons and microglia, resulting in ongoing low-grade inflammation. Traditionally, the pathways of Aβ production and neuroinflammation have been considered independently; however, recent studies suggest that these processes may converge to promote the pathology associated with AD. Here we review the importance of inflammation and microglia in AD development and effects of inflammatory responses on cellular pathways of neurons, including Aβ generation.

Related collections

Most cited references 56

Record: found
Abstract: found
Article: not found

Microglia Function in the Central Nervous System During Health and Neurodegeneration.

Marco Colonna, Oleg Butovsky (2017)

Microglia are resident cells of the brain that regulate brain development, maintenance of neuronal networks, and injury repair. Microglia serve as brain macrophages but are distinct from other tissue macrophages owing to their unique homeostatic phenotype and tight regulation by the central nervous system (CNS) microenvironment. They are responsible for the elimination of microbes, dead cells, redundant synapses, protein aggregates, and other particulate and soluble antigens that may endanger the CNS. Furthermore, as the primary source of proinflammatory cytokines, microglia are pivotal mediators of neuroinflammation and can induce or modulate a broad spectrum of cellular responses. Alterations in microglia functionality are implicated in brain development and aging, as well as in neurodegeneration. Recent observations about microglia ontogeny combined with extensive gene expression profiling and novel tools to study microglia biology have allowed us to characterize the spectrum of microglial phenotypes during development, homeostasis, and disease. In this article, we review recent advances in our understanding of the biology of microglia, their contribution to homeostasis, and their involvement in neurodegeneration. Moreover, we highlight the complexity of targeting microglia for therapeutic intervention in neurodegenerative diseases. Expected final online publication date for the Annual Review of Immunology Volume 35 is April 26, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

0 comments Cited 813 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

APP processing and synaptic function.

Flavio Kamenetz, Taisuke Tomita, Helen V. Hsieh … (2003)

A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.

0 comments Cited 440 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation

Jae-Woong Lee, Yong Kyung Lee, Dong Yuk … (2008)

Background Alzheimer's disease (AD) is characterized by extensive loss of neurons in the brain of AD patients. Intracellular accumulation of beta-amyloid peptide (Aβ) has also shown to occur in AD. Neuro-inflammation has been known to play a role in the pathogenesis of AD. Methods In this study, we investigated neuro-inflammation and amyloidogenesis and memory impairment following the systemic inflammation generated by lipopolysaccharide (LPS) using immunohistochemistry, ELISA, behavioral tests and Western blotting. Results Intraperitoneal injection of LPS, (250 μg/kg) induced memory impairment determined by passive avoidance and water maze tests in mice. Repeated injection of LPS (250 μg/kg, 3 or 7 times) resulted in an accumulation of Aβ1–42 in the hippocampus and cerebralcortex of mice brains through increased β- and γ-secretase activities accompanied with the increased expression of amyloid precursor protein (APP), 99-residue carboxy-terminal fragment of APP (C99) and generation of Aβ1–42 as well as activation of astrocytes in vivo. 3 weeks of pretreatment of sulindac sulfide (3.75 and 7.5 mg/kg, orally), an anti-inflammatory agent, suppressed the LPS-induced amyloidogenesis, memory dysfunction as well as neuronal cell death in vivo. Sulindac sulfide (12.5–50 μM) also suppressed LPS (1 μg/ml)-induced amyloidogenesis in cultured neurons and astrocytes in vitro. Conclusion This study suggests that neuro-inflammatory reaction could contribute to AD pathology, and anti-inflammatory agent could be useful for the prevention of AD.

0 comments Cited 287 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Title: Immunology & Cell Biology

Abbreviated Title: Immunol Cell Biol

Publisher: Wiley

ISSN (Print): 0818-9641

ISSN (Electronic): 1440-1711

Publication date Created: November 02 2019

Publication date Created: January 2020

Publication date (Electronic): November 20 2019

Publication date (Print): January 2020

Volume: 98

Issue: 1

Pages: 28-41

Affiliations

[1 ]Department of Biochemistry and Molecular Biology Bio21 Molecular Science and Biotechnology Institute The University of Melbourne Parkville VIC Australia

[2 ]Department of Neurodegenerative Disease and Geriatric Psychiatry University of Bonn Bonn Germany

[3 ]German Center for Neurodegenerative Diseases Bonn Germany