Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes

Zuroff, Leah; Daley, David A.; Black, Keith L.; Koronyo‐Hamaoui, Maya

doi:10.1007/s00018-017-2463-7

Cited by 221 publications

(187 citation statements)

References 400 publications

(523 reference statements)

Supporting

Mentioning

181

Contrasting

Unclassified

Order By: Relevance

“…In addition to the effect seen on MMP‐9, we also found that resveratrol may facilitate the activation of microglia/macrophages, thereby inducing long‐term adaptive immunity that may be clinically beneficial . Since chronic neuroinflammation likely contributes to the focal encephalopathy causing clinical dementia, activation of specific microglia/macrophages may be neuroprotective . As AD progresses, innate immune cells, such as resident microglia and macrophages, exhibit dysfunctional or senescent profiles characterized by impaired phagocytosis.…”

Section: Resveratrol For the Treatment Of Alzheimer's Diseasementioning

confidence: 99%

Resveratrol for Alzheimer's disease

Sawda

Moussa

Turner

2017

Annals of the New York Academy of Sciences

219

132

View full text Add to dashboard Cite

The amyloid hypothesis suggests that the progressive accumulation and deposition of central nervous system amyloid with aging is the proximate cause of Alzheimer’s disease (AD). Thus, targeting molecular mechanisms of aging may represent a viable treatment approach. Caloric restriction prevents diseases of aging, including AD, in animal models, perhaps by activation of sirtuins. The sirtuins (such as mammalian SIRT1) are deacetylases that link energy balance (NAD+/NADH) to regulation of gene transcription. Resveratrol is a potent activator of SIRT1, and thus may mimic caloric restriction to prevent diseases of aging. We conducted a randomized, double blind, placebo-controlled, phase II trial of resveratrol for individuals with mild to moderate AD. Resveratrol (1) is detectable in cerebrospinal fluid (at low nanomolar levels), (2) is safe and well tolerated, (3) alters AD biomarker trajectories, (4) preserves blood–brain barrier integrity, and (5) modulates the CNS immune response. Further studies are needed to determine the safety and efficacy of resveratrol and the validity of this approach in the treatment and prevention of AD and other diseases of aging.

show abstract

Section: Resveratrol For the Treatment Of Alzheimer's Diseasementioning

confidence: 99%

Resveratrol for Alzheimer's disease

Sawda

Moussa

Turner

2017

Annals of the New York Academy of Sciences

219

132

View full text Add to dashboard Cite

show abstract

“…A large body of experimental evidence supports the view that amyloid plaques are (Taylor et al, ) key to driving AD pathogenesis through activation of both the innate and the adaptive immune pathways (Hardy & Selkoe, ). The ensuing neuroinflammatory response sustains the production and release of neurotoxic and inflammatory mediators (Schwartz & Deczkowska, ; Su, Bai, & Zhang, ) through the activation of microglia and astrocytes, causing neuronal cell death (Meda et al, ; Zuroff, Daley, Black, & Koronyo‐Hamaoui, ) and the release of inflammatory neurotransmitters and ROS (Tansey, McCoy, & Frank‐Cannon, ).…”

Section: Introductionmentioning

confidence: 99%

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Cristiano

Volpicelli

Lippiello

et al. 2019

British J Pharmacology

106

View full text Add to dashboard Cite

Background and purpose Alzheimer's disease (AD) is a common neurodegenerative disease characterized by a neuroinflammatory state, and to date, there is no cure and its treatment represents a large unmet clinical need. The involvement of Th17 cells in the pathogenesis of AD‐related neuroinflammation has been reported in several studies. However, the role of the cytokine, IL‐17 has not been well addressed. Herein, we investigate the effects of IL‐17 neutralizing antibody (IL‐17Ab) injected by i.c.v. or intranasal (IN) routes on amyloid‐β (Aβ)‐induced neuroinflammation and memory impairment in mice. Experimental approach Aβ1–42 was injected into cerebral ventricles of adult CD1 mice. These mice received IL‐17Ab via i.c.v. either at 1 h prior to Aβ1–42 injection or IN 5 and 12 days after Aβ1–42 injection. After 7 and 14 days of Aβ1–42 administration, we evaluated olfactory, spatial and working memory and performed biochemical analyses on whole brain and specific brain areas. Key results Pretreatment with IL‐17Ab, given, i.c.v., markedly reduced Aβ1–42‐induced neurodegeneration, improved memory function, and prevented the increase of pro‐inflammatory mediators in a dose‐dependent manner at 7 and 14 days. Similarly, the double IN administration of IL‐17Ab after Aβ1–42 injection reduced neurodegeneration, memory decline, and the levels of proinflammatory mediators and cytokines. Conclusion and implications These findings suggest that the IL‐17Ab reduced neuroinflammation and behavioural symptoms induced by Aβ. The efficacy of IL‐17Ab IN administration in reducing Aβ1–42 neurodegeneration points to a possible future therapeutic approach in patients with AD. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

show abstract

“…This data suggests that gal3 is a critical alarmin that amplifies the Aβ-induced proinflammatory response. Since inefficient clearance of Aβ may play a determinant role in AD pathogenesis [76], we analyzed the effect of gal3 in two major mechanisms associated to Aβ clearance: fAβ phagocytosis and IDE-1 levels, a key metalloprotease involved in Aβ degradation by microglia [25,28,39]. Gal3 was able to reduce Aβ phagocytosis, and gal3 deficiency increased IDE-1 levels, suggesting a detrimental role of gal3 in Aβ clearance.…”

Section: Discussionmentioning

confidence: 99%

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

Boza-Serrano¹,

Ruiz

Sánchez-Varo³

et al. 2018

Preprint

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, intraneuronal tau neurofibrillary tangles and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice, and found specifically expressed in microglia associated with Aβ plaques. Single nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated to an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data demonstrated the requirement of gal3 to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Electron microscopy of gal3 in AD mice demonstrated i) a preferential expression of gal3 by plaque-associated microglia, ii) its presence in the extracellular space and iii) its association to Aβ plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure Aβ. Importantly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of insoluble Aβ aggregates that were absent when gal3 was lacking. High-resolution microscopy (STORM) demonstrated close co-localization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 CRD domain. Furthermore, gal3 stimulated the TREM2-DAP12 signaling pathway. In conclusion, we provide evidence that gal3 is a central regulator of microglial immune response in AD. It drives proinflammatory activation and Aβ aggregation, as well as acting as an endogenous ligand to TREM2, a key receptor driving microglial response under disease conditions. Gal3 inhibition may, hence, be a potential pharmacological approach to counteract AD. #Corresponding Authors:Tomas Deierborg (tomas.deierborg@med.lu.se), Jose Luis Venero (jlvenero@us.es) and Antonio Boza-Serrano (antonio.boza_serrano@med.lu.se). Keywords:Alzheimer's disease, Galectin-3, TREM2, Microglial, Amyloid Aggregation. classical hallmarks of AD include the formation of amyloid-beta (Aβ) plaque deposits and of neurofibrillary tangles (NFT) containing abnormal hyperphosphorylation of tau. Over the course of the disease, the deposition of Aβ and the formation of the NFTs appear to be correlated with the on-going hippocampal neurodegeneration [7]. Hippocampal neurodegeneration has a negative effect on the cognitive ability of patients, especially short-term memory, which is impaired. The mechanisms triggering the deposition of the Aβ or the formation of NFT are currently unclear. However, several mechanisms and factors have been suggested to be involved in ...

show abstract

Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes

Cited by 221 publications

References 400 publications

Resveratrol for Alzheimer's disease

Resveratrol for Alzheimer's disease

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

Contact Info

Product

Resources

About