Secreted endogenous macrosomes reduce Aβ burden and ameliorate Alzheimer’s disease

Abstract

Innovative therapeutic strategies are urgently needed for Alzheimer’s disease (AD) due to the increasing size of the aging population and the lack of effective drug treatment. Here, we report the therapeutic effects of extracellular vesicles (EVs) secreted by microglia, including macrosomes and small EVs, on AD-associated pathology. Macrosomes strongly inhibited β-amyloid (Aβ) aggregation and rescued cells from Aβ misfolding–induced cytotoxicity. Furthermore, macrosome administration reduced Aβ plaques and ameliorated cognitive impairment in mice with AD. In contrast, small EVs slightly promoted Aβ aggregation and did not improve AD pathology. Proteomic analysis of small EVs and macrosomes revealed that macrosomes harbor several important neuroprotective proteins that inhibit Aβ misfolding. In particular, the small integral membrane protein 10–like protein 2B in macrosomes has been shown to inhibit Aβ aggregation. Our observations provide an alternative therapeutic strategy for the treatment of AD over conventional ineffective drug treatments.

A highly sensitive nanochannel device for the detection of SUMO1 peptides

“…1 H-1 H nuclear magnetic resonance (NMR) spectra provided the details of binding between CP-1 and DG12. 52,53 First, the chemical shi attribution of each H proton in CP-1 and DG12 was assigned according to the two-dimensional 1 H-1 H (correlation spectroscopy) COSY and 13 C-1 H (heteronuclear singular quantum correlation) HSQC NMR spectra (Fig. S21-S25 in the ESI †).…”

Application of Multiomics Approach to Investigate the Therapeutic Potentials of Stem Cell-derived Extracellular Vesicle Subpopulations for Alzheimer’s Disease

“…There is mounting experimental evidence indicating size-dependent beneficial effects of different EV subpopulation. While in some reports beneficial effects of small EVs have been shown 11,12 , others indicated the superior beneficial effects of large EVs for alleviating molecular phenotypes of AD 13 . These observations were attributed to the size and size distribution of EV subpopulation, ultimately effecting their cargo contents and their therapeutic properties 14,15 .…”

“…Particularly, therapeutic MSCs-derived exosomes have been shown to exhibit neuroprotective effects by regulating pathways associated with oxidative stress, neuroinflammation, apoptosis, reduced NFT and Amyloid plaques on cell and animal models of AD 11,12 . Interestingly, large EVs have been shown to reduce pathological changes and restore homeostasis in a mouse model of AD more effectively 13 . In addition, previous studies have highlighted that EVs isolated by different methods yield different size distribution and dependent on the size EVs carry distinct cargo that affects their features 14,15 .…”

Hybrid Membrane‐Coated Nanoparticles for Precise Targeting and Synergistic Therapy in Alzheimer's Disease

“…A recent study revealed that microglial macrosomes reduce the amyloid burden and ameliorate AD, but microsomes have completely opposite effects. [ 48 ] It is important to note whether the original cell membranes or EVs are damaged during preparation. Furthermore, the long‐term safety and potential immunogenicity of these nanomaterials must be thoroughly evaluated.…”