Silica Nanodepletors: Targeting and Clearing Alzheimer's β‐Amyloid Plaques

Abstract

Abnormal accumulation of β-amyloid (Aβ) peptide aggregates in the brain is a major hallmark of Alzheimer's disease (AD). Aβ aggregates interfere with neuronal communications, ultimately causing neuronal damage and brain atrophy. Much effort has been made to develop AD treatments that suppress Aβ aggregate formation, thereby attenuating Aβ-induced neurotoxicity. Here, the design of Aβ nanodepletors consisting of ultralarge mesoporous silica nanostructures and anti-Aβ single-chain variable fragments, with the goal of targeting and eliminating aggregative Aβ monomers, is reported. The Aβ nanodepletors impart a notable decline in Aβ aggregate formation, resulting in significant mitigation of Aβ-induced neurotoxicity in vitro. Furthermore, stereotaxic injections of Aβ nanodepletors into the brain of an AD mouse model system successfully suppress Aβ plaque formation in vivo up to ≈30%, suggesting that Aβ nanodepletors can serve as a promising antiamylodoisis material.aged 65 and older are living with AD, [4] which accounts for an estimated 60-80% of dementia.Accumulation of extracellular β-amyloid (Aβ) plaques and intracellular tau proteinderived neurofibrillary tangles are major hallmarks of Alzheimer-associated brain damages in AD patients. These features are being explored from the perspective of pathological diagnosis and clinical treatment of AD. [5,6] Aβ monomers, which are derived from the cleavage of amyloid precursor protein by βand γ-secretase, [7] assemble into toxic Aβ oligomers and aggregates having cross β-sheet-rich secondary structures that induce neuronal damages. [8][9][10][11] Ultimately, the self-assembly process leads to the deposition of amyloid plaques, a strong and stable network that is difficult to break. Hence, removing monomeric Aβ at the early stage of dementia is thought to be a promising strategy for slowing the progression of AD. [12][13][14][15][16] Here, we report an Aβ-depleting nanostructure (denoted hereafter as Aβ nanodepletors) that can selectively capture and clear Aβ peptide monomers in brain (Scheme 1).

Functional nanoassemblies for the diagnosis and therapy of Alzheimer's diseases

“…Song et al, 2014) or neuroprotective peptide (M. Huang et al, 2015) can effectively neutralize toxic Aβ species and promote microglia to engulf Aβ plaques, thereby mitigating the symptoms of AD mice. Moreover, MSN‐based nanoassembly surface‐conjugated with anti‐Aβ scFv effectively reduced ~30% of Aβ plaques and ~20% of soluble Aβ42 in the hippocampus/cortex region of AD brain, successfully preventing the nucleation of Aβ aggregates at the initial stage of the self‐assembly process (Figure 4a–f) (Jung et al, 2020). Recently, a small‐sized nanocomposite (14 ± 4 nm) prepared by wrapping a protein molecule with Aβ‐binding peptides (KLVFF)‐containing polymer layer was reported.…”

“…(a) Schematic illustration of the Aβ nanodepletors' anti‐amyloidogenic capabilities; (b and c) brain sections images of Aβ plaques stained by (b) Thioflavin S and (c) anti‐Aβ antibody followed by secondary antibody containing Alexa Fluor 568; (d and e) imaging analyses of Aβ plaques using (d) ThS stained images and (e) immunostained images; (f) ELISA measurements of relative Aβ42 levels of BSA‐decorated nanostructure injected brains and Aβ nanodepletor injected brains; (g) schematic illustration of MCNA synthesis; (h) schematic illustration of Aβ capture and magnetic separation by MCNAs. (i) MCNA concentration‐dependent Aβ peptide capture efficiency; (j) plasma Aβ concentrations measured before and after the Aβ cleansing treatment with MCNAs (1.8 × 10 −3 m [Fe]); (k) ROS levels in the plasma samples nontreated (transgenic, Tg) or treated with different types of NPs Source : (a–f) Reprinted with permission from Jung et al (2020) Copyright 2020 Wiley; (g–k) reprinted with permission from D. Kim et al, 2019 Copyright 2019 Wiley…”

NIR‐II Hydrogen‐Bonded Organic Frameworks (HOFs) Used for Target‐Specific Amyloid‐β Photooxygenation in an Alzheimer's Disease Model

“…Numerous studies have focused on potential methods that can disturb Ab assembly based on the amyloid hypothesis in AD pathology. [6][7][8][9][10][11][12][13][14][15] Among them, photooxygenation of Ab has emerged as apowerful approach for irreversibly suppressing Ab aggregation with notable advantages of low invasiveness,r emote controllability,a nd high spatiotemporal precision. [16,17] However,p revalent photosensitizers are confined to ultraviolet or visible light which cannot penetrate thick brain tissues.…”

Nitrogen‐Doped Carbonized Polymer Dots: A Potent Scavenger and Detector Targeting Alzheimer's β‐Amyloid Plaques

“…Many inhibitors against amyloidosis have been reported, including small molecules, [9][10][11] peptides, [12,13] proteins, [14,15] and nanomaterials. [16][17][18][19][20][21] Their properties in electrostatic, hydrogen bonding (H-bonding), π-π stacking, and hydrophobic interactions with Aβ are utilized to disrupt the process of Aβ aggregation and alleviate Aβ toxicity. Of various nanoparticles, graphene quantum dots (GQDs) have been recently employed for detecting Aβ monomers; [22] improving learning and memory capabilities; [23] inhibiting Aβ, α-synuclein, or human islet amyloid polypeptide aggregation; [24][25][26] and triggering disaggregation of α-synuclein fibrils.…”