Therapeutic Targets in Innate Immunity to Tackle Alzheimer’s Disease DOI Creative Commons

Maria L. Serradas,

Yingying Ding,

Paula Martorell

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(17), P. 1426 - 1426

Published: Aug. 26, 2024

There is an urgent need for effective disease-modifying therapeutic interventions Alzheimer's disease (AD)-the most prevalent cause of dementia with a profound socioeconomic burden. Most clinical trials targeting the classical hallmarks this disease-β-amyloid plaques and neurofibrillary tangles-failed, showed discrete effects, or were accompanied by concerning side effects. has been ongoing search novel targets. Neuroinflammation, now widely recognized as hallmark all neurodegenerative diseases, proven to be major contributor AD pathology. Here, we summarize role neuroinflammation in pathogenesis progression discuss potential targets such microglia, TREM2, complement system, inflammasomes, cytosolic DNA sensors. We also present overview studies specific innate immune system components, highlighting progress field drug research while bringing attention delicate nature modulations AD.

Language: Английский

The Lectin Pathway of the Complement System—Activation, Regulation, Disease Connections and Interplay with Other (Proteolytic) Systems DOI Open Access
József Dobó, Andrea Kocsis, Bence Farkas

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1566 - 1566

Published: Jan. 26, 2024

The complement system is the other major proteolytic cascade in blood of vertebrates besides coagulation–fibrinolytic system. Among three main activation routes complement, lectin pathway (LP) has been discovered latest, and it still subject intense research. Mannose-binding (MBL), collectins, ficolins are collectively termed as pattern recognition molecules (PRMs) LP, they responsible for targeting LP to molecular patterns, e.g., on bacteria. MBL-associated serine proteases (MASPs) effectors, while proteins (MAps) have regulatory functions. Two protease components, MASP-1 MASP-2, trigger activation, third component, MASP-3, involved function alternative (AP) complement. Besides their functions within system, certain components secondary (“moonlighting”) functions, embryonic development. They also contribute coagulation, some might tumor suppressing roles. Uncontrolled can progression many diseases (e.g., stroke, kidney diseases, thrombotic complications, COVID-19). In most cases, implicated. this review, we summarize history pathway, introduce describe its regulation, roles cascade, connections direct cellular effects. Special emphasis placed disease non-canonical components.

Language: Английский

Citations

22
Beyond the Norm: The emerging interplay of complement system and extracellular matrix in the tumor microenvironment DOI Creative Commons
Andrea Balduit, Chiara Agostinis, Roberta Bulla

et al.

Seminars in Immunology, Journal Year: 2025, Volume and Issue: 77, P. 101929 - 101929

Published: Jan. 9, 2025

Language: Английский

Citations

5
Inflammation in the Peripheral Nervous System after Injury DOI Creative Commons

Dandan Gu,

Yiming Xia,

Zihan Ding

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(6), P. 1256 - 1256

Published: June 5, 2024

Nerve injury is a common condition that occurs as result of trauma, iatrogenic injury, or long-lasting stimulation. Unlike the central nervous system (CNS), peripheral (PNS) has strong capacity for self-repair and regeneration. Peripheral nerve results in degeneration distal axons myelin sheaths. Macrophages Schwann cells (SCs) can phagocytose damaged cells. Wallerian (WD) makes whole axon structure degenerate, creating favorable regenerative environment new axons. After macrophages, neutrophils other are mobilized recruited to site necrotic debris. Pro-inflammatory anti-inflammatory factors involved inflammatory response provide microenvironment regeneration regulate effects inflammation on body through relevant signaling pathways. Previously, was thought be detrimental body, but further research shown appropriate promotes regeneration, formation. On contrary, excessive cause tissue damage pathological changes, even lead neurological diseases. Therefore, after various interact with cytokines chemokines promote repair by inhibiting negative harnessing positive specific ways at times. Understanding interaction between neuroinflammation provides several therapeutic ideas improve

Language: Английский

Citations

12
Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine’s antidepressant effects? DOI

Brandi Quintanilla,

Carlos A. Zarate, Anilkumar Pillai

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(9), P. 2849 - 2858

Published: April 4, 2024

Language: Английский

Citations

8
The complement system in neurodegenerative diseases DOI Creative Commons

Jacqui Nimmo,

Robert A. J. Byrne, Nikoleta Daskoulidou

et al.

Clinical Science, Journal Year: 2024, Volume and Issue: 138(6), P. 387 - 412

Published: March 1, 2024

Abstract Complement is an important component of innate immune defence against pathogens and crucial for efficient complex disposal. These core protective activities are dependent in large part on properly regulated complement-mediated inflammation. Dysregulated complement activation, often driven by persistence activating triggers, a cause pathological inflammation numerous diseases, including neurological diseases. Increasingly, this has become apparent not only well-recognized neuroinflammatory diseases like multiple sclerosis but also neurodegenerative neuropsychiatric where was previously either ignored or dismissed as secondary event. There now rapidly growing body evidence implicating that cannot be comprehensively addressed brief review. Here, we will focus the ‘classical’ such Alzheimer’s disease Parkinson’s disease, two other neurodegeneration neglected feature implicated, namely, schizophrenia, neurodevelopmental disorder with many mechanistic features neurodegeneration, sclerosis, demyelinating major progressive decline. We discuss driver pathology these diverse address briefly potential pitfalls anti-complement drug therapy

Language: Английский

Citations

7
C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer’s disease mouse model DOI Creative Commons
Nicole D. Schartz, Heidi Yahan Liang, Klébea Carvalho

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 15, 2024

Alzheimer's disease (AD) is the leading cause of dementia in older adults, and need for effective, sustainable therapeutic targets imperative. The complement pathway has been proposed as a target. C5aR1 inhibition reduces plaque load, gliosis, memory deficits animal models, however, cellular bases underlying this neuroprotection were unclear. Here, we show that antagonist PMX205 improves outcomes Arctic48 mouse model AD. A combination single cell nucleus RNA-seq analysis hippocampi derived from males females identified neurotoxic disease-associated microglia clusters Arctic mice are C5aR1-dependent, while microglial genes associated with synapse organization transmission learning overrepresented PMX205-treated mice. also reduced astrocyte gene expression, but protective responses to injury unchanged. promoted mRNA-predicted signaling pathways between brain types growth repair, suppressing inflammatory pathways. Finally, although hippocampal load was unaffected, prevented short-term female In conclusion, prevents cognitive loss, limits detrimental glial polarization permitting neuroprotective responses, well leaving most functions intact, making antagonism an attractive strategy

Language: Английский

Citations

6
The schizophrenia risk gene C4 induces pathological synaptic loss by impairing AMPAR trafficking DOI Creative Commons
Rhushikesh A. Phadke, Alison Brack, Luke A. Fournier

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

Neuroimmune interactions play a significant role in regulating synaptic plasticity both the healthy and diseased brain. The complement pathway, an extracellular proteolytic cascade, exemplifies these interactions. Its activation triggers microglia-dependent elimination via receptor 3 (CR3). Current models of pathological activity brain propose that accelerated loss resulting from overexpression C4 (C4-OE), gene associated with schizophrenia, follows this pathway. Here, we report C4-mediated cortical hypoconnectivity is CR3-independent. Instead, C4-OE impaired GluR1 trafficking through intracellular mechanism involving endosomal protein SNX27, loss. Moreover, circuit alterations prefrontal cortex, region neuropsychiatric disorders, were rescued by increasing neuronal levels which identify as interacting partner neuroimmune protein. Our results link excessive to endo-lysosomal pathway altering plasticity.

Language: Английский

Citations

6
Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia DOI Creative Commons
Wioleta M. Zelek, Ryan J. Bevan, B. Paul Morgan

et al.

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 118, P. 355 - 363

Published: March 12, 2024

Complement is dysregulated in the brain Alzheimer's Disease and mouse models of disease. Each complement derived effectors, opsonins, anaphylatoxins membrane attack complex (MAC), have been implicated as drivers disease but their relative contributions remain unclarified. Here we focussed on MAC, a lytic pro-inflammatory effector, AppNL−G−F amyloidopathy model. To test role back-crossed to generate mice deficient C7, an essential MAC component. C7 deficiency ablated formation, reduced synapse loss amyloid load improved cognition compared complement-sufficient at 8–10 months age. Adding back caused increased formation acute synapses C7-deficient mice. explore whether was viable therapeutic target, C7-blocking monoclonal antibody administered systemically for one month aged 8–9 months. Treatment deposition, density cognitive performance isotype control-treated The findings implicate driver pathology highlight potential inhibition level therapy

Language: Английский

Citations

4
Apolipoprotein E ε4 exacerbates microglia-mediated complement-dependent synapse loss caused by neuronal Tpk deficiency DOI Open Access

P du,

Boru Jin, Zijie Wang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract Thiamine pyrophosphokinse-1 (TPK) is a key enzyme that converts thiamine to functional diphosphate (TDP). TPK insufficiency and hence TDP reduction in neurons induced by amyloid-β deposition diabetes, an independent risk factor of Alzheimer’s disease (AD), recapitulate multi-pathophysiological features the brain mice, similar those human AD. Apolipoprotein E ε 4 allele ( APOE4 ) most well-known genetic for Clinical trials boosting using benfotiamine, derivative significantly elevates level encrythrocytes, have shown inferior clinical efficacies carriers compared non-APOE4 carriers. Clarifying relationship between expression characteristics AD Tpk deficiency imperative. Here, we find humanized didn’t directly affect but markedly aggravates behavior abnormalities Tpk- cKO mice. Pathologically, mice with knock-in (AE-cKO mice) exhibit more synapse loss than only Transcriptomics pathologic analysis identified promoted overactivation microglia transition disease-associated phagocytosis state via complement-mediated pathway. Further, C3aR antagonist repressed synaptic elimination AE-cKO Our results demonstrate exacerbates dysfunction through microglia-mediated complement-dependent elimination. These findings provide important insights into role pathogenesis

Language: Английский

Citations

0
Transcriptome analysis reveals that the injection of mesenchymal stem cells remodels extracellular matrix and complement components of the brain through PI3K/AKT/FOXO1 signaling pathway in a neuroinflammation mouse model DOI Creative Commons

Zhihao Xu,

Keqin Liu,

Guoqing Zhang

et al.

Genomics, Journal Year: 2025, Volume and Issue: 117(3), P. 111033 - 111033

Published: March 22, 2025

Language: Английский

Citations

0