Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer's Disease Mice

By S. Hickman, Elizabeth K. Allison, J. El Khoury. Journal of Neuroscience, 2008

1,297 citations recorded by the source corpus.

Early microglial accumulation in Alzheimer's disease (AD) delays disease progression by promoting clearance of β-amyloid (Aβ) before formation of senile plaques. However, persistent Aβ accumulation despite increasing microglial numbers suggests that the ability of microglia to clear Aβ may decrease with age and progression of AD pathology. To determine the effects of aging and Aβ deposition on microglial ability to clear Aβ, we used quantitative PCR to analyze gene expression in freshly isolated adult microglia from 1.5-, 3-, 8-, and 14-month-old transgenic PS1-APP mice, an established mouse model of AD, and from their nontransgenic littermates. We found that microglia from old PS1-APP mice, but not from younger mice, have a twofold to fivefold decrease in expression of the Aβ-binding scavenger receptors scavenger receptor A (SRA), CD36, and RAGE (receptor for advanced-glycosylation endproducts), and the Aβ-degrading enzymes insulysin, neprilysin, and MMP9, compared with their littermate controls. In contrast, PS1-APP microglia had a 2.5-fold increase in the proinflammatory cytokines IL-1β (interleukin-1β) and tumor necrosis factor α (TNFα), suggesting that there is an inverse correlation between cytokine production and Aβ clearance. In support of this possibility, we found that incubation of cultured N9 mouse microglia with TNFα decreased the expression of SRA and CD36 and reduced Aβ uptake. Our data indicate that, although early microglial recruitment promotes Aβ clearance and is neuroprotective in AD, as disease progresses, proinflammatory cytokines produced in response to Aβ deposition downregulate genes involved in Aβ clearance and promote Aβ accumulation, therefore contributing to neurodegeneration. Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration.

Subfields: Clinical Biochemistry, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/7fd0dad6c01b5ba051d3f9ed67bf275b88d0be2b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Neurology

In Physiology

Citations in the corpus

The role of microglia in amyloid clearance from the AD brain (2010, background): “reported that the levels of IDE, NEP and MMP9 were dramatically reduced in older mice with the concomitant upregulation of proinflammatory cytokines (Hickman et al. 2008).”
The blood-brain barrier in Alzheimer's disease (2017, neutral): “…activation of microglia is accompanied by diminished phagocytosis and the more abundant secretion of pro-in ﬂ ammatory cytokines, leading to the accumulation of A β and the ampli ﬁ cation of neuroin ﬂ ammation (El Khoury et al., 2007; Hickman et al., 2008; Krabbe et al., 2013; Heneka et al., 2015).”
TREM2 lipid sensing sustains microglia response in an Alzheimer’s disease model (2015, neutral): “At late stages of AD, microglia may paradoxically contribute to the disease by releasing pro-inflammatory cytokines in response to Aβ deposition (El Khoury et al., 2007; Hickman et al., 2008).”
Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, background): “In contrast, their capacity of proinflammatory cytokine production is unaffected, contributing to an exacerbation of AD pathology including Aβ accumulation and neuronal damage.(170,171) To compensate the impaired clearance of Aβ, peripheral macrophages are recruited to the brain in an effort to clea”
iPSC-derived human microglia-like cells to study neurological diseases (2017, neutral): “In AD, microglia cluster around beta-amyloid plaques highlighting their inability to clear beta-amyloid (Hickman et al., 2008, Liu et al., 2010).”
Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies (2024, background): “174 ,175 A β also causes the formation and activation of the NLRP3 in ﬂ ammasome within microglia, which releases ASC specks that bind rapidly to A β in promoting A β aggregates and the spread of A β pathology.”
Overview of General and Discriminating Markers of Differential Microglia Phenotypes (2020, background): “Another important microglial multimeric complex protein is ferritin, which is responsible for iron storage and its homeostasis and is upregulated due to microglia activation (Holland et al., 2018).”