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"Drug-Carrier" Synergy Therapy for Amyloid-β Clearance and Inhibition of Tau Phosphorylation via Biomimetic Lipid Nanocomposite Assembly.

ABSTRACT: Amyloid-β (Aβ) toxicity is considered to be companioned by Tau phosphorylation in Alzheimer's disease (AD). The clinical AD therapy is usually subjected to low blood-brain barrier (BBB) penetration and complex interaction mechanisms between Aβ and phosphorylated Tau. A "Drug-Carrier" synergy therapy is herein designed to simultaneously target Aβ and Tau-associated pathways for AD treatment. To imitate natural nanoparticle configuration, the endogenous apolipoprotein A-I and its mimicking peptide 4F fused angiopep-2 (Ang) are sequentially grafted onto lipid nanocomposite (APLN), providing liberty of BBB crossing and microglia targeted Aβ clearance. For synergy treatment, methylene blue (MB) is further assembled into APLN (APLN/MB) for Tau aggregation inhibition. After intravenous administration, the optimized density (5 wt%) of Ang ligands dramatically enhances APLN/MB intracerebral shuttling and accumulation, which is 2.15-fold higher than that Ang absent-modification. The site-specific release of MB collaborates APLN to promote Aβ capture for microglia endocytosis clearance and reduce p-Tau level by 25.31% in AD pathogenesis. In AD-Aβ-Tau bearing mouse models, APLN/MB can relieve AD symptoms, rescue neuron viability and cognitive functions. Collectively, it is confirmed that "Drug-Carrier" synergy therapy of APLN/MB is a promising approach in the development of AD treatments.

SUBMITTER: Han G

PROVIDER: S-EPMC9108666 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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"Drug-Carrier" Synergy Therapy for Amyloid-β Clearance and Inhibition of Tau Phosphorylation via Biomimetic Lipid Nanocomposite Assembly.

Han Guochen G Bai Kaiwen K Yang Xiaoyu X Sun Chenhua C Ji Yi Y Zhou Jianping J Zhang Huaqing H Ding Yang Y

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20220320 14

Amyloid-β (Aβ) toxicity is considered to be companioned by Tau phosphorylation in Alzheimer's disease (AD). The clinical AD therapy is usually subjected to low blood-brain barrier (BBB) penetration and complex interaction mechanisms between Aβ and phosphorylated Tau. A "Drug-Carrier" synergy therapy is herein designed to simultaneously target Aβ and Tau-associated pathways for AD treatment. To imitate natural nanoparticle configuration, the endogenous apolipoprotein A-I and its mimicking peptide ...[more]

PMID: 35307993

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Project description:ObjectiveEpilepsy can be comorbid with cognitive impairments. Recent evidence suggests the possibility that cognitive decline in epilepsy may be associated with mechanisms typical of Alzheimer's disease (AD). Neuropathological hallmarks of AD have been found in brain biopsies surgically resected from patients with drug-resistant epilepsies. These include hyperphosphorylation of the tau protein (p-tau) that aggregates into neuropil threads (NT) or neurofibrillary tangles (NFT), as well as the presence of β-amyloid (Aβ) deposits. While recent studies agree on these AD neuropathological findings in epilepsy, some contrast in their correlation to cognitive decline. Thus, to further address this question we determined the abundance of p-tau and Aβ proteins along with their association with cognitive function in 12 cases of refractory epilepsy.MethodsCortical biopsies surgically extracted from the temporal lobes of patients with refractory epilepsy were processed for immunohistology and enzyme-linked immunoassays to assess distribution and levels, respectively, of p-tau (Antibodies: Ser202/Thr205; Thr205; Thr181) and Aβ proteins. In parallel, we measured the activation of mechanistic target of rapamycin (mTOR) via p-S6 (Antibodies: Ser240/244; Ser235/236). Pearson correlation coefficient analysis determined associations between these proteins and neurophysiological scores for full-scale intelligence quotient (FSIQ).ResultsWe found a robust presence of p-tau (Ser202/Thr205)-related NT and NFT pathology, as well as Aβ deposits, and p-S6 (Ser240/244; Ser235/236) in the epilepsy biopsies. We found no significant correlations between p-tau (Thr205; Thr181), Aβ, or mTOR markers with FSIQ scores, although some correlation coefficients were modest to strong.SignificanceThese findings strongly support the existence of hyperphosphorylated tau protein and Aβ deposits in patients with human refractory epilepsy. However, their relation to cognitive decline is still unclear and requires further investigation.

Dataset Information

"Drug-Carrier" Synergy Therapy for Amyloid-β Clearance and Inhibition of Tau Phosphorylation via Biomimetic Lipid Nanocomposite Assembly.

Publications

"Drug-Carrier" Synergy Therapy for Amyloid-β Clearance and Inhibition of Tau Phosphorylation via Biomimetic Lipid Nanocomposite Assembly.

Similar Datasets

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