Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer’s disease mouse model DOI Creative Commons

Alex Orlowski,

Joseph Karippaparambil,

Jean‐Michel Paumier

et al.

eNeuro, Journal Year: 2024, Volume and Issue: 11(12), P. ENEURO.0445 - 24.2024

Published: Dec. 1, 2024

Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques disrupted axonal lysosome transport has been implicated worsening Alzheimer's pathology. Our prior studies have revealed loss of Adaptor protein-4 (AP-4) complex function, linked primarily to spastic paraplegia (HSP), leads a similar lysosomes structures we term “AP-4 dystrophies.” Surprisingly, these AP-4 dystrophies were also characterized by enrichment components APP processing machinery, β-site cleaving enzyme 1 (BACE1) Presenilin 2. examining whether the abnormal buildup resulting from could lead amyloidogenesis function an disease model resulted strong increase size abundance hippocampus corpus callosum as well increased microglial association with plaques. Interestingly, found further secretase, BACE1, swellings Alzheimer mice lacking compared those having normal suggestive amyloidogenic under this condition. Additionally, exacerbation plaque pathology was region specific it did not cortex. The burden dystrophies/AP-4 higher cortex, establishing critical role AP-4-dependent maturation regulating protein processing.

Language: Английский

Microglia and amyloid plaque formation in Alzheimer's disease – Evidence, possible mechanisms, and future challenges DOI Creative Commons
Stefanie Fruhwürth, Henrik Zetterberg, Søren R. Paludan

et al.

Journal of Neuroimmunology, Journal Year: 2024, Volume and Issue: 390, P. 578342 - 578342

Published: April 5, 2024

Alzheimer's disease (AD) is a neurodegenerative characterized by cognitive decline that severely affects patients and their families. Genetic environmental risk factors, such as viral infections, synergize to accelerate the aging-associated neurodegeneration. factors for late-onset AD (LOAD), which accounts most cases, are predominantly implicated in microglial immune cell functions. As such, microglia play major role amyloid beta (Aβ) plaque (the pathological hallmark of AD) formation. This review aims provide an overview current knowledge regarding Aβ formation, well impact on morphological functional diversity plaques. Based this discussion, we seek identify challenges opportunities field with potential therapeutic implications.

Language: Английский

Citations

19
Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease DOI Creative Commons
Nóra Baligács, Giulia Albertini, Sarah C. Borrie

et al.

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

Published: Dec. 5, 2024

Abstract The role of microglia in the amyloid cascade Alzheimer’s disease (AD) is debated due to conflicting findings. Using a genetic and pharmacological approach we demonstrate that depletion before amyloid-β (Aβ) plaque deposition, leads reduction numbers neuritic dystrophy, confirming their initiation. Transplanting human restores Aβ formation. While reduces insoluble levels, soluble concentrations stay consistent, challenging view clear Aβ. In later stages, microglial decreases compaction increases suggesting protective role. Human with TREM2 R47H/R47H mutation exacerbate pathology, emphasizing importance non-reactive initiation cascade. Adaptive immune ( Rag2 -/- ) does not affect microglia’s impact on These findings clarify reports, identifying as key drivers raise questions about optimal therapeutic strategies for AD.

Language: Английский

Citations

5
Microglia degrade Alzheimer’s amyloid-beta deposits extracellularly via digestive exophagy DOI Creative Commons

Rudy G Jacquet,

Fernando González Ibáñez, Katherine Picard

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(12), P. 115052 - 115052

Published: Dec. 1, 2024

Language: Английский

Citations

5
Anti-Aβ immunotherapy-mediated amyloid clearance attenuates microglial activation without inducing exhaustion at residual plaques DOI Creative Commons
Lis de Weerd, Selina Hummel, Stephan A. Müller

et al.

Published: April 17, 2025

Abstract Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer’s disease. Efficient clearance has been proven in clinical trials testing anti-Aβ antibodies, with the impact on endpoints correlating extent removal. However, treatment is associated adverse side-effects, such as oedema haemorrhages, which are potentially linked induced immune response. To improve safety profile these molecules, it imperative understand consequences antibody cell function. Here, we investigated effects long-term chronic microglial response APP-SAA triple knock-in mouse model. Mice were treated weekly from 4-8 months age. Long-term results a robust dose-dependent removal pathology, higher efficiency for removing diffuse over dense-core plaques. Analysis CSF proteome indicates reduction markers neurodegeneration including Tau α-Synuclein, well related proteins. Bulk RNA-seq revealed decrease brain-wide disease-associated (DAM) glycolytic gene expression, supported by parallel glucose uptake protein levels Triggering receptor myeloid cells 2 (Trem2) protein, major involved DAM activation microglia. In contrast, around remaining plaques remains high regardless dose. addition, microglia surrounding display increase clustering selective antigen presenting signalling These findings demonstrate that mediated Aβ leads dose dependent neurodegeneration, while at residual combined phenotype suggests continued Figure Graphical abstract: Schematic overview mice created BioRender.com

Language: Английский

Citations

0
Development of Granzyme B-targeted Smart Positron Emission Tomography Probes for Monitoring Tumor Early Response to Immunotherapy DOI
Jiayu Fu,

Hongjie Xi,

Shuyue Cai

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(29), P. 18910 - 18921

Published: July 13, 2024

Granzyme B is an immune-related biomarker that closely correlates with cytotoxic T lymphocytes (CTLs), and hence detecting the expression level of granzyme can provide a dependable scheme for clinical immune response assessment. In this study, two positron emission tomography (PET) probes [18F]SF-M-14 [18F]SF-H-14 targeting are designed based on intramolecular cyclization scaffold SF. respond to glutathione (GSH) conduct self-assemble into nanoaggregates enhance retention probe at target site. Both prepared high radiochemical purity (>98%) stability in PBS mouse serum. 4T1 cells cocultured lymphocytes, reach maximum uptake 6.71 ± 0.29 3.47 0.09% ID/mg 0.5 h, respectively, but they remain below 1.95 0.22 1.47 0.21% without coculture lymphocytes. vivo PET imaging shows tumor 4T1-tumor-bearing mice after immunotherapy significantly higher (3.5 times) than untreated group. The treated BEC was 4.08 0.16 3.43 0.12% ID/g, while 1.04 0.79 1.41 0.11% respectively. These results indicate both have great potential early evaluation efficacy.

Language: Английский

Citations

3
Potential Alzheimer’s disease drug targets identified through microglial biology research DOI
Izabela Lepiarz‐Raba, Taufik Hidayat, Anthony J. Hannan

et al.

Expert Opinion on Drug Discovery, Journal Year: 2024, Volume and Issue: 19(5), P. 587 - 602

Published: April 8, 2024

Introduction Microglia, the primary immune cells in brain, play multifaceted roles Alzheimer's disease (AD). Microglia can potentially mitigate pathological progression of AD by clearing amyloid beta (Aβ) deposits brain and through neurotrophic support. In contrast, disproportionate activation microglial pro-inflammatory pathways, as well excessive elimination healthy synapses, exacerbate neurodegeneration AD. The challenge, therefore, lies discerning precise regulation contrasting properties to harness their therapeutic potential

Language: Английский

Citations

2
Small Molecule Decoy of Amyloid-β Aggregation Blocks Activation of Microglia-Like Cells DOI
Sho Oasa, Gefei Chen, Marianne Schultzberg

et al.

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 101(3), P. 787 - 796

Published: Sept. 6, 2024

Aggregated forms of the amyloid-β (Aβ) peptides which form protofibrils and fibrils in brain are signatures Alzheimer's disease (AD). Aggregates also recognized by microglia, early phases may be protective later contribute to pathology. We have identified several small molecules, decoys interfere with Aβ oligomerization induce other aggregation trajectories leading aggregated macrostructures non-toxic.

Language: Английский

Citations

2
Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimers disease mouse model DOI Creative Commons

Alex Orlowski,

Joseph Karippaparambil,

Jean‐Michel Paumier

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 1, 2024

Abstract Lysosomes and related precursor organelles robustly build up in swollen axons that surround amyloid plaques disrupted axonal lysosome transport has been implicated worsening Alzheimer’s pathology. Our prior studies have revealed loss of Adaptor protein-4 (AP-4) complex function, linked primarily to Spastic Paraplegia (HSP), leads a similar lysosomes structures we term “AP-4 dystrophies”. Surprisingly, these AP-4 dystrophies were also characterized by enrichment components APP processing machinery, β-site cleaving enzyme 1 (BACE1) Presenilin 2. examining whether the abnormal resulting from could lead amyloidogenesis function an disease model resulted strong increase size abundance hippocampus corpus callosum as well increased microglial association with plaques. Interestingly, found further secretase, BACE1, swellings Alzheimer mice lacking compared those having normal suggestive amyloidogenic under this condition. Additionally, exacerbation plaque pathology was region-specific it did not cortex. The burden dystrophies/AP-4 higher cortex, establishing critical role -dependent maturation regulating protein processing. Significance Statement A major pathological feature is accumulation near sites Lysosome thought contribute production. In fact, genetic perturbation arrests exacerbates mechanisms control molecular composition endolysosomes produce Abeta, however, are fully understood. Axonal build-up emerging common other neurodegenerative disorders such Hereditary but its relevance production unknown. We find HSP caused adaptor buildup differs some content, still contributes amyloidogenesis. This demonstrates different perturbations leading changes heterogeneous pool can converge on

Language: Английский

Citations

1
Disease modifying effects of the amyloid-beta protofibril-selective antibody mAb158 in aged Tg2576 transgenic mice DOI Creative Commons
Biljana Rizoska,

Olof Zachrisson,

Paulina Appelkvist

et al.

Molecular and Cellular Neuroscience, Journal Year: 2024, Volume and Issue: 130, P. 103950 - 103950

Published: June 18, 2024

Amyloid beta (Aβ) peptides, which aggregate to form neocortical plaques in Alzheimer's disease, exist states that range from soluble monomers and oligomers/protofibrils insoluble fibrillar amyloid. The present study evaluated the effects of mAb158, a mouse monoclonal antibody version lecanemab preferentially binds Aβ protofibrils, aged transgenic mice (Tg2576) with pathology. Female Tg2576 (12 months old) received weekly intraperitoneal mAb158 (35 mg/kg) or vehicle for 4 weeks 18 weeks, without subsequent 12-week off-treatment period. protofibril levels were significantly lower mAb158-treated animals at both while longer treatment duration (18 weeks) was required observe Aβ42 brain fractions plaque load. Following period, comparison vehicle- demonstrated levels, load remained animals, as compared age-matched controls. However, there significant increase accumulation after cessation. Thus, repeated first reduced within treatment, then followed by reduction amyloid pathology treatment. These maintained 12 final dose, indicating had disease-modifying effect on this model. In addition, progressed discontinuation supports importance continued maintain

Language: Английский

Citations

1
Human brain organoids containing microglia that have arisen innately adapt to a β-amyloid challenge better than those in which microglia are integrated by co-culture DOI Creative Commons
Tyler J. Wenzel,

Joseph D. Desjarlais,

Darrell D. Mousseau

et al.

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 13, 2024

Alzheimer disease (AD) is a heterogenous and multifactorial disease, its pathology partly driven by microglia their activated phenotype. Brain organoids (BOs) are gaining prominence as relevant model of the human brain for study AD; however, BOs commonly devoid microglia. To overcome this limitation, current protocols incorporate through either (1) co-culture (BO co-culture), or (2) molecular manipulation at critical windows BO development to have arise innately innate cultures). It currently unclear whether incorporated into these two differ in function.

Language: Английский

Citations

1