Amyloid-β specific regulatory T cells attenuate Alzheimer’s disease pathobiology in APP/PS1 mice

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Дек. 18, 2023

Abstract Background Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions required disease-specific targeting and improved outcomes. To address this need, amyloid-beta (Aβ) was conferred Treg responses by engineering receptor (TCR) specific Aβ (TCR A β ). The TCR Ab were developed from effector (Teff) clones. ability Tregs expressing a transgenic -Tregs) reduce burden, transform regulatory cells, reverse disease-associated neurotoxicity proved beneficial in an animal model Alzheimer’s disease. Methods -Tregs generated CRISPR-Cas9 knockout endogenous consequent incorporation identified reactive Teff monoclones. Antigen confirmed MHC-Aβ-tetramer staining. Adoptive transfer mice chimeric mouse-human amyloid precursor protein mutant human presenilin-1 followed measured behavior, immune, immunohistochemical Results expressed Aβ-specific TCR. led sustained suppression, reduced microglial reaction, loads. 18 F-fluorodeoxyglucose radiolabeled -Treg homed facilitating specificity. Reduction load associated with cognitive functions. Conclusions restored homeostasis, learning memory, supporting increased benefit immunotherapy AD. Graphical

Язык: Английский

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Ushering in a New Era of Alzheimer Disease Therapy

JAMA, Год журнала: 2023, Номер 330(6), С. 503 - 503

Опубликована: Июль 17, 2023

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Язык: Английский

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Brain Shrinkage in Anti–β-Amyloid Alzheimer Trials

Neurology, Год журнала: 2023, Номер 100(20), С. 941 - 942

Опубликована: Март 27, 2023

One of the puzzling observations from anti–amyloid-β therapeutic trials for Alzheimer disease (AD) has been that treated arms fail to show preservation brain volume. In this issue Neurology ®, Alves et al.1 presented a meta-analysis therapies and agents do not slow rate volume loss. Depending on class drug, these new can even accelerate loss whole-brain hippocampal increase ventricular This association seen with some beta-secretase inhibitors several antiamyloid monoclonal antibodies.

Язык: Английский

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Alzheimer’s Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3892 - 3892

Опубликована: Март 31, 2024

The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that protein amyloid-beta cause of disease. Two antibodies, aducanumab and lecanemab, have been approved by U.S. Food Drug Administration, while a third, donanemab, under review. main argument FDA approvals presumed therapy-induced removal cerebral deposits. Lecanemab donanemab are also thought to some statistical delay in determination cognitive decline. However, clinical efficacy less than with conventional treatment, selection amyloid-positive trial patients non-specific amyloid-PET imaging, uncertain amyloids trials cast doubt on this anti-Alzheimer's antibody therapy hence hypothesis, calling more thorough investigation negative impact type brain.

Язык: Английский

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New horizons in the diagnosis and management of Alzheimer’s Disease in older adults

Age and Ageing, Год журнала: 2024, Номер 53(2)

Опубликована: Фев. 1, 2024

Abstract Alzheimer’s Disease (ad) is the most common cause of dementia, and in addition to cognitive decline, it directly contributes physical frailty, falls, incontinence, institutionalisation polypharmacy older adults. Increasing availability clinically validated biomarkers including cerebrospinal fluid positron emission tomography assess both amyloid tau pathology has led a reconceptualisation ad as clinical–biological diagnosis, rather than one based purely on clinical phenotype. However, co-pathology frequent adults which influence accuracy biomarker interpretation. Importantly, some with positive or pathological may never experience impairment dementia. These strides towards achieving an accurate diagnosis are occurring alongside recent phase 3 trial results reporting statistically significant effects anti-amyloid Disease-Modifying Therapies (DMTs) disease severity early ad. real-world benefit these DMTs not clear concerns remain regarding how will translate populations, potential adverse (including amyloid-related imaging abnormalities), can be severe healthcare systems readiness afford deliver appropriate populations. Here, we review advances diagnostic classification future treatment living Advocating for access more must done so holistic gerontologically attuned fashion, geriatricians advocating enhanced multi-component multi-disciplinary care all This includes those across spectrum potentially ineligible emerging DMTs.

Язык: Английский

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