SSK1-Loaded Neurotransmitter-Derived Nanoparticles for Alzheimer's Disease Therapy via Clearance of Senescent Cells.

Age is a significant contributor to the onset of AD. Senolysis has been recently demonstrated to ameliorate aging-associated diseases that showing a great potential in AD therapy. However, due to the presence of BBB, the anti-AD activity of senolytics are significantly diminished. SSK1 is a prodrug that can be activated by ß-gal, a lysosomal enzyme commonly upregulated in senescent cells, and thus selectively eliminates senescent cells. Furthermore, the level of ß-gal is significantly correlated with conventional AD genes from clinical sequencing data. SSK1-loaded neurotransmitter -derived lipid nanoparticles are herein developed (SSK1-NPs) that revealing good BBB penetration and bioavailability of in the body. At the brain lesion, SSK1-NP treatment significantly reduces the expression of genes associated with senescence, induced senescent cells elimination, decreased amyloid-beta accumulation, and eventually improve cognitive function of aged AD mice. SSK1-NPs, a novel nanomedicine displaying potent anti-AD activity and excellent safety profile, provides a promising strategy for AD therapy.

Systemic Administration of Neurotransmitter-Derived Lipidoids-PROTACs-DNA Nanocomplex Promotes Tau Clearance and Cognitive Recovery for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) poses a significant burden on the economy and healthcare systems worldwide. Although the pathophysiology of AD remains debatable, its progression is strongly correlated with the accumulation of tau aggregates. Therefore, tau clearance from brain lesions can be a promising strategy for AD therapy. To achieve this, the present study combined proteolysis-targeting chimera (PROTAC), a novel protein-degradation technique that mediates degradation of target proteins via the ubiquitin-proteasome system, and a neurotransmitter-derived lipidoid (NT-lipidoid) nanoparticle delivery system with high blood-brain barrier-penetration activity, to generate a novel nanomedicine named NPD. Peptide 1, a cationic tau-targeting PROTAC is loaded onto the positively charged nanoparticles using DNA-intercalation technology. The resulting nanomedicine displayed good encapsulation efficiency, serum stability, drug release profile, and blood-brain barrier-penetration capability. Furthermore, NPD potently induced tau clearance in both cultured neuronal cells and the brains of AD mice. Moreover, intravenous injection of NPD led to a significant improvement in the cognitive function of the AD mice, without any remarkable abnormalities, thereby supporting its clinical development. Collectively, the novel nanomedicine developed in this study may serve as an innovative strategy for AD therapy, since it effectively and specifically induces tau protein clearance in brain lesions, which in turn enhances cognition.

Cell primitive-based biomimetic nanomaterials for Alzheimer's disease targeting and therapy.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, which is not just confined to the older population. Although developments have been made in AD treatment, various limitations remain to be addressed. These are partly contributed by biological hurdles, such as the blood-brain barrier and peripheral side effects, as well as by lack of carriers that can efficiently deliver the therapeutics to the brain while preserving their therapeutic efficacy. The increasing AD prevalence and the unavailability of effective treatments have encouraged researchers to develop improved, convenient, and affordable therapies. Functional materials based on primitive cells and nanotechnology are emerging as attractive therapeutics in AD treatment. Cell primitives possess distinct biological functions, including long-term circulation, lesion site targeting, and immune suppression. This review summarizes the challenges in the delivery of AD drugs and recent advances in cell primitive-based materials for AD treatment. Various cell primitives, such as cells, extracellular vesicles, and cell membranes, are presented together with their distinctive biological functions and construction strategies. Moreover, future research directions are discussed on the basis of foreseeable challenges and perspectives.

Postoperative hematoma in cervical spondylosis patient complicated with Huntington's disease: Case report and literature review.

Hematoma is a life-threatening complication of anterior surgery in cervical spondylosis patients. Herein, we report a cervical spondylosis patient complicated with Huntington's disease, who developed unexpected neck hematoma after anterior cervical discectomy and fusion (ACDF) surgical treatment. During the debridement, we found no noticeable vessel lesions and concluded that the occurrence of postoperative hematoma might be due to the drainage displacement caused by excessive uncontrolled movements of the neck after the operation. The patient recovered well, and further literature review suggests that chorea secondary to Huntington's disease likely increases mechanical stress on the cervical spine, indicating an internal relationship between degenerative cervical spondylosis and Huntington's disease. Cervical spondylotic patients complicated with Huntington's disease can be treated with surgical intervention but need to be immobilized and under close observation.

Engineered mesenchymal stem cell-derived extracellular vesicles: A state-of-the-art multifunctional weapon against Alzheimer's disease.

With the increase of population aging, the number of Alzheimer's disease (AD) patients is also increasing. According to current estimates, approximately 11% of people over 65 suffer from AD, and that percentage rises to 42% among people over 85. However, no effective treatment capable of decelerating or stopping AD progression is available. Furthermore, AD-targeted drugs composed of synthetic molecules pose concerns regarding biodegradation, clearance, immune response, and neurotoxicity. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are essential intercellular communication mediators holding great promise as AD therapeutics owing to their biocompatibility, versatility, effortless storage, superior safety, and the ability to transport messenger and noncoding RNAs, proteins, lipids, DNAs, and other bioactive compounds derived from cells. The functionalisation and engineering strategies of MSC-EVs are highlighted (e.g. preconditioning, drug loading, surface modification, and artificial EV fabrication), which could improve AD treatment by multiple therapeutic effects, including clearing abnormal protein accumulation and achieving neuroprotection and immunomodulatory effects. Herein, this review summarises state-of-the-art strategies to engineer MSC-EVs, discusses progress in their use as AD therapeutics, presents the perspectives and challenges associated with the related clinical applications, and concludes that engineered MSC-EVs show immense potential in AD therapy.

Biomembrane-Derived Nanoparticles in Alzheimer's Disease Therapy: A Comprehensive Review of Synthetic Lipid Nanoparticles and Natural Cell-Derived Vesicles.

Current therapies for Alzheimer's disease used in the clinic predominantly focus on reducing symptoms with limited capability to control disease progression; thus, novel drugs are urgently needed. While nanoparticles (liposomes, high-density lipoprotein-based nanoparticles) constructed with synthetic biomembranes have shown great potential in AD therapy due to their excellent biocompatibility, multifunctionality and ability to penetrate the BBB, nanoparticles derived from natural biomembranes (extracellular vesicles, cell membrane-based nanoparticles) display inherent biocompatibility, stability, homing ability and ability to penetrate the BBB, which may present a safer and more effective treatment for AD. In this paper, we reviewed the synthetic and natural biomembrane-derived nanoparticles that are used in AD therapy. The challenges associated with the clinical translation of biomembrane-derived nanoparticles and future perspectives are also discussed.

Recent Advancements in Strategies for Abnormal Protein Clearance in Alzheimer's Disease.

Alzheimer's disease (AD) is an intricate neurodegenerative disease with chronic and progressive development whose typical neuropathological features encompass senile plaques and neurofibrillary tangles, respectively formed by the extracellular deposition of amyloid-beta (Aß) and the intracellular accumulation of hyperphosphorylated tau protein in the brain, particularly in limbic and cortical regions. The pathological changes are considered to be caused by the loss of Aß and tau protein clearance mechanisms under pathological conditions, which leads to an imbalance between the rates of clearance and production. Consequently, the main strategies for treating AD aim to reduce the production of Aß and hyperphosphorylated tau protein in the brain, inhibit their accumulation, or accelerate their clearance. Although drugs utilizing these therapeutic strategies have been studied successively, their therapeutic effects have generally been less than ideal. Fortunately, recent advances have been made in clearance strategies for these abnormally expressed proteins, including immunotherapies and nanomedicines targeting Aß or tau, which could represent an important breakthrough for treating AD. Here, we review recent development of the strategies for the removal of abnormal proteins and provide new ideas and methods for treating AD.

Nanoparticles-based anti-aging treatment of Alzheimer's disease.

Age is the strongest risk factor for Alzheimer's disease (AD). In recent years, the relationship between aging and AD has been widely studied, with anti-aging therapeutics as the treatment for AD being one of the mainstream research directions. Therapeutics targeting senescent cells have shown improvement in AD symptoms and cerebral pathological changes, suggesting that anti-aging strategies may be a promising alternative for AD treatment. Nanoparticles represent an excellent approach for efficiently crossing the blood-brain barrier (BBB) to achieve better curative function and fewer side effects. Thereby, nanoparticles-based anti-aging treatment may exert potent anti-AD therapeutic efficacy. This review discusses the relationship between aging and AD and the application and prospect of anti-aging strategies and nanoparticle-based therapeutics in treating AD.

Recent Progress Towards Vaccines and Antibody-based Therapies Against Alzheimer's Disease.

Alzheimer's disease (AD), one of the progressive neurodegenerative disorders, is characterized by clinical features such as memory loss, acquired skill loss, apraxia, and interpersonal and social communication disorders. The AD hallmarks at the neuropathological level include intracellular neurofibrillary tangles constituted by the hyperphosphorylated tau protein as well as the senile extracellular plaques dominated by the amyloid-ß (Aß) deposits. At present, AD treatment that mainly targeted towards improving symptoms and effective drugs to delay or stop disease progression is lacking. Vaccines and antibody-based therapies are a type of natural, synthetic, and gene recombinant biological product that treat or prevent disease progression by stimulating specific or non-specific immune responses. Compared with traditional targeted drugs, vaccines and antibodybased therapies have better safety and effectiveness and can even maintain the expression and stability of Aß and Tau proteins in patients for a long time. Logically, vaccines and antibody-based therapies are somewhat different from traditional drugs because these drugs can achieve the therapeutic effect of AD by activating immune cells and regulating the immune system of patients themselves, thereby clearing disease-related proteins and long-term survival. Complete cure is also observed in some patients after receiving the immunotherapy. Currently available vaccines and antibody-based therapies mainly target Aß and phosphorylated tau proteins. There are 44 vaccines and antibodybased therapies for AD, among which nine drugs are discontinued, three drugs are inactive, eleven drugs are in clinical phase 1, twelve drugs are in clinical phase 2, and seven drugs are in clinical phase 3. Currently, no vaccines and antibody-based therapies have been approved for AD treatment. In this paper, we review and analyse the research progress of vaccines and antibody-based therapies that are used to treat AD.