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Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer's disease pathology.

ABSTRACT: Evidence suggests that beta-amyloid (Aβ)-induced phosphorylation/aggregation of tau protein plays a critical role in the degeneration of neurons and development of Alzheimer's disease (AD), the most common cause of dementia affecting the elderly population. Many studies have pursued a variety of small molecules, including nanoparticles conjugated with drugs to interfere with Aβ and/or tau aggregation/toxicity as an effective strategy for AD treatment. We reported earlier that FDA approved PLGA nanoparticles without any drug can attenuate Aβ aggregation/toxicity in cellular/animal models of AD. In this study, we evaluated the effects of native PLGA on Aβ seed-induced aggregation of tau protein using a variety of biophysical, structural and spectroscopic approaches. Our results show that Aβ_1-42 seeds enhanced aggregation of tau protein in the presence and absence of heparin and the effect was attenuated by native PLGA nanoparticles. Interestingly, PLGA inhibited aggregation of both 4R and 3R tau isoforms involved in the formation of neurofibrillary tangles in AD brains. Furthermore, Aβ seed-induced tau aggregation in the presence of arachidonic acid was suppressed by native PLGA. Collectively, our results suggest that native PLGA nanoparticles can inhibit the Aβ seed-induced aggregation of different tau protein isoforms highlighting their therapeutic implication in the treatment of AD.

SUBMITTER: Paul PS

PROVIDER: S-EPMC10762165 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer's disease pathology.

Paul Pallabi Sil PS Patel Tark T Cho Jae-Young JY Yarahmady Allan A Khalili Aria A Semenchenko Valentyna V Wille Holger H Kulka Marianna M Mok Sue-Ann SA Kar Satyabrata S

Scientific reports 20240102 1

Evidence suggests that beta-amyloid (Aβ)-induced phosphorylation/aggregation of tau protein plays a critical role in the degeneration of neurons and development of Alzheimer's disease (AD), the most common cause of dementia affecting the elderly population. Many studies have pursued a variety of small molecules, including nanoparticles conjugated with drugs to interfere with Aβ and/or tau aggregation/toxicity as an effective strategy for AD treatment. We reported earlier that FDA approved PLGA n ...[more]

PMID: 38167993

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Project description:Conversion of β-amyloid (Aβ) peptides from soluble random-coil to aggregated protein enriched with β-sheet-rich intermediates has been suggested to play a role in the degeneration of neurons and development of Alzheimer's disease (AD) pathology. Aggregation of Aβ peptide can be prompted by a variety of environmental factors including temperature which can influence disease pathogenesis. Recently, we reported that FDA-approved unconjugated poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles can have beneficial effects in cellular and animal models of AD by targeting different facets of the Aβ axis. In this study, using biochemical, structural and spectroscopic analyses, we evaluated the effects of native PLGA on temperature-dependent Aβ aggregation and its ability to protect cultured neurons from degeneration. Our results show that the rate of spontaneous Aβ1-42 aggregation increases with a rise in temperature from 27 to 40 °C and PLGA with 50:50 resomer potently inhibits Aβ aggregation at all temperatures, but the effect is more profound at 27 °C than at 40 °C. It appears that native PLGA, by interacting with the hydrophobic domain of Aβ1-42, prevents a conformational shift towards β-sheet structure, thus precluding the formation of Aβ aggregates. Additionally, PLGA triggers disassembly of matured Aβ1-42 fibers at a faster rate at 40 °C than at 27 °C. PLGA-treated Aβ samples can significantly enhance viability of cortical cultured neurons compared to neurons treated with Aβ alone by attenuating phosphorylation of tau protein. Injection of native PLGA is found to influence the breakdown/clearance of Aβ peptide in the brain. Collectively, these results suggest that PLGA nanoparticles can inhibit Aβ aggregation and trigger disassembly of Aβ aggregates at temperatures outside the physiological range and can protect neurons against Aβ-mediated toxicity thus validating its unique therapeutic potential in the treatment of AD pathology.

Project description:BackgroundAccumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer's disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6-18 and 77E9 against tau 184-195 on tau and amyloid-β (Aβ) pathologies and cognition in triple-transgenic (3×Tg)-AD mice at mild to moderate stages of the disease.MethodsWe immunized 12-month-old female 3×Tg-AD mice with two to six or seven intravenous weekly doses of 15 μg of mouse monoclonal antibody 43D, 77E9, a combination of one-half dose each of 43D and 77E9, or as control of mouse immunoglobulin G (IgG). Age-matched wild-type mice treated with mouse IgG or a mixture of 43D and 77E9 were also used as controls. The effect of immunization with tau antibodies on tau and Aβ pathologies was assessed by Western blot and immunofluorescence analysis, and the effect on cognition was analyzed by using Morris water maze, one-trial novel object recognition, and novel object location tasks.ResultsWe found that two doses of 43D and 77E9 reduced total tau but had no significant impact on hyperphosphorylation of tau. However, six doses of 43D reduced levels of both total tau and tau hyperphosphorylated at Ser262/356 and Ser396/404 sites in the hippocampus. Importantly, both 43D and 77E9 antibodies rescued spatial memory and short-term memory impairments in 3×Tg-AD mice. The beneficial effect of 43D and 77E9 antibodies on cognitive performance was sustained up to 3 months after the last dose. Six doses of immunization with 43D also decreased amyloid precursor protein (APP) level in CA1 and amyloid plaques in subiculum, and showed a trend toward reducing Aβ40 and Aβ42 in the forebrain. Immunization with 43D increased levels of complement components C1 and C9 and resulted in activation of microglia, especially surrounding Aβ plaques.ConclusionsThese findings suggest the potential of passive immunization targeting proximal N-terminal domain tau 6-18 as a disease-modifying approach to AD and related tauopathies.

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Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer's disease pathology.

Publications

Native PLGA nanoparticles attenuate Aβ-seed induced tau aggregation under in vitro conditions: potential implication in Alzheimer's disease pathology.

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