Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and is part of a massive and growing health care burden that is destroying the cognitive function of more than 50 million individuals worldwide. Today, therapeutic options are limited to approaches with mild symptomatic benefits. The failure in developing effective drugs is attributed to, but not limited to the highly heterogeneous nature of AD with multiple underlying hypotheses and multifactorial pathology. In addition, targeted drug delivery to the central nervous system (CNS), for the diagnosis and therapy of neurological diseases like AD, is restricted by the challenges posed by blood-brain interfaces surrounding the CNS, limiting the bioavailability of therapeutics. Research done over the last decade has focused on developing new strategies to overcome these limitations and successfully deliver drugs to the CNS. Nanoparticles, that are capable of encapsulating drugs with sustained drug release profiles and adjustable physiochemical properties, can cross the protective barriers surrounding the CNS. Thus, nanotechnology offers new hope for AD treatment as a strong alternative to conventional drug delivery mechanisms. In this review, the potential application of nanoparticle based approaches in Alzheimer’s disease and their implications in therapy is discussed.

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Astrocytic transporters in Alzheimer's disease

Biochemical Journal ◽

10.1042/bcj20160505 ◽

2017 ◽

Vol 474 (3) ◽

pp. 333-355 ◽

Cited By ~ 7

Author(s):

Chris Ugbode ◽

Yuhan Hu ◽

Benjamin Whalley ◽

Chris Peers ◽

Marcus Rattray ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Neurological Diseases ◽

Current Evidence ◽

Specific Targeting ◽

Disease Modifying Therapies ◽

The Central Nervous System ◽

Disease Modifying ◽

And Function

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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Aging of the Nigrostriatal Pathway in Humans

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100037847 ◽

1987 ◽

Vol 14 (S3) ◽

pp. 424-427 ◽

Cited By ~ 18

Author(s):

Donald B. Calne ◽

R.F. Peppard

Keyword(s):

Alzheimer’S Disease ◽

Parkinson’S Disease ◽

Alzheimer's Disease ◽

Parkinson's Disease ◽

Neurological Diseases ◽

Nigrostriatal Pathway ◽

Toxic Damage ◽

Degenerative Disorders ◽

The Central Nervous System ◽

Genetically Determined

ABSTRACT:Progressive degeneration of functionally related groups of neurons occurs in certain infective, toxic, nutritional and genetically determined neurological diseases. It also takes place in normal aging, and several of the regions that undergo selective decay with the passage of time seem to be the same target regions that are afflicted in degenerative disorders such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis (ALS). Infective etiology is relatively easy to exclude by a combination of immunological tests and transfer experiments. Genetic causation can be rendered unlikely when large kindreds are available for study. Nutritional deprivation and acute or subacute toxicity are accessible to explanation by examining the environment. The most difficult mechanism of pathogenesis to refute is chronic toxic damage, where the lesion may derive from long-term exposure to a relatively widespread noxious agent or agents. Variations in involvement of individuals within a population may stem from differing capacities to activate or inactivate a toxin. Inherent in this concept of etiology is recognition that compensatory potential within the central nervous system may contribute to prolonged existence of subclinical lesions so that a latent period may exist for several decades, between causal event and the onset of symptoms. Furthermore, progressive clinical deterioration may take place even though the cause may have been transient, many years before. The histological features associated with Parkinson's disease, Alzheimer's disease and ALS may be nonspecific indicators of neuronal “illness”, there being a predilection for certain morphological markers to appear more frequently in particular circumstances and particular regions associated with the pathology of particular diseases.

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Paired helical filaments (PHF) in rats: An experimental animal model for Alzheimer's disease

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100128493 ◽

1987 ◽

Vol 45 ◽

pp. 842-843

Author(s):

V.J.A. Montpetit ◽

S. Dancea ◽

S.W. French ◽

D.F. Clapin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Model ◽

Paired Helical Filaments ◽

Ethanol Intoxication ◽

Drg Neurons ◽

Critical Difference ◽

Suitable Animal Model ◽

The Central Nervous System ◽

Chronic Ethanol Intoxication

A continuing problem in Alzheimer research is the lack of a suitable animal model for the disease. The absence of neurofibrillary tangles of paired helical filaments is the most critical difference in the processes by which the central nervous system ages in most species other than man. However, restricting consideration to single phenomena, one may identify animal models for specific aspects of Alzheimer's disease. Abnormal fibers resembling PHF have been observed in dorsal root ganglia (DRG) neurons of rats in a study of chronic ethanol intoxication and spontaneously in aged rats. We present in this report evidence that PHF-like filaments occur in ethanol-treated rats of young age. In control animals lesions similar in some respects to our observations of cytoskeletal pathology in pyridoxine induced neurotoxicity were observed.Male Wistar BR rats (Charles River Labs) weighing 350 to 400 g, were implanted with a single gastrostomy cannula and infused with a liquid diet containing 30% of total calories as fat plus ethanol or isocaloric dextrose.

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Neuropeptides in Alzheimer’s Disease: An Update

Current Alzheimer Research ◽

10.2174/1567205016666190503152555 ◽

2019 ◽

Vol 16 (6) ◽

pp. 544-558 ◽

Cited By ~ 1

Author(s):

Carla Petrella ◽

Maria Grazia Di Certo ◽

Christian Barbato ◽

Francesca Gabanella ◽

Massimo Ralli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Potential Role ◽

Brain Distribution ◽

Brain Areas ◽

Small Proteins ◽

Current Review ◽

The Central Nervous System ◽

Available Information

Neuropeptides are small proteins broadly expressed throughout the central nervous system, which act as neurotransmitters, neuromodulators and neuroregulators. Growing evidence has demonstrated the involvement of many neuropeptides in both neurophysiological functions and neuropathological conditions, among which is Alzheimer’s disease (AD). The role exerted by neuropeptides in AD is endorsed by the evidence that they are mainly neuroprotective and widely distributed in brain areas responsible for learning and memory processes. Confirming this point, it has been demonstrated that numerous neuropeptide-containing neurons are pathologically altered in brain areas of both AD patients and AD animal models. Furthermore, the levels of various neuropeptides have been found altered in both Cerebrospinal Fluid (CSF) and blood of AD patients, getting insights into their potential role in the pathophysiology of AD and offering the possibility to identify novel additional biomarkers for this pathology. We summarized the available information about brain distribution, neuroprotective and cognitive functions of some neuropeptides involved in AD. The main focus of the current review was directed towards the description of clinical data reporting alterations in neuropeptides content in both AD patients and AD pre-clinical animal models. In particular, we explored the involvement in the AD of Thyrotropin-Releasing Hormone (TRH), Cocaine- and Amphetamine-Regulated Transcript (CART), Cholecystokinin (CCK), bradykinin and chromogranin/secretogranin family, discussing their potential role as a biomarker or therapeutic target, leaving the dissertation of other neuropeptides to previous reviews.

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Transdermal Drug Delivery Systems and their Potential in Alzheimer’s Disease Management

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200618150046 ◽

2020 ◽

Vol 19 (5) ◽

pp. 360-373 ◽

Cited By ~ 1

Author(s):

Panoraia I. Siafaka ◽

Ece Ö. Bülbül ◽

Gökce Mutlu ◽

Mehmet E. Okur ◽

Ioannis D. Karantas ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Drug Delivery ◽

Alzheimer's Disease ◽

Disease Management ◽

Transdermal Drug Delivery ◽

Drug Delivery Systems ◽

Delivery Systems ◽

Oral Dosage ◽

Transdermal Administration ◽

Transdermal Drug Delivery Systems

Alzheimer's disease is a neuropathological disease with symptoms such as language problems, confusion as to place or time, loss of interest in activities, which were previously enjoyed, behavioral changes, and memory loss. Alzheimer's disease and other types of dementia affect almost 46.8 million people globally and are estimated to strike about 131.5 million people in 2050. It has been reported that Alzheimer's is the sixth main cause of mortality. The most used drugs, which are currently approved by the Food, and Drug Administration for Alzheimer’s disease are donepezil, rivastigmine, galantamine, memantine, and the combination of donepezil and memantine. However, most of the drugs present various adverse effects. Recently, the transdermal drug delivery route has gained increasing attention as an emerging tool for Alzheimer's disease management. Besides, transdermal drug delivery systems seem to provide hope for the management of various diseases, due to the advantages that they offer in comparison with oral dosage forms. Herein, the current advancements in transdermal studies with potent features to achieve better Alzheimer's disease management are presented. Many researchers have shown that the transdermal systems provide higher efficiency since the first-pass hepatic metabolism effect can be avoided and a prolonged drug release rate can be achieved. In summary, the transdermal administration of Alzheimer's drugs is an interesting and promising topic, which should be further elaborated and studied.

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Nanotechnology Based Delivery Systems of Drugs Currently Used to Treat Alzheimer’s Disease

Nanoscience &Nanotechnology-Asia ◽

10.2174/2210681209666190228143636 ◽

2020 ◽

Vol 10 (3) ◽

pp. 228-247

Author(s):

Niloufar Choubdar ◽

Sara Avizheh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Polymeric Nanoparticles ◽

Biological Fluids ◽

Delivery Systems ◽

Original Research ◽

Sustained Drug Release ◽

The Past ◽

Site Of Action ◽

Therapeutic Compound

Alzheimer’s Disease (AD) is one of the most common forms of dementia affecting over 46 million people, according to AD International. Over the past few decades, there has been considerable interest in developing nanomedicines. Using nanocarriers, the therapeutic compound could be delivered to the site of action where it gets accumulated. This accumulation, therefore, reduces the required doses for therapy. Alternatively, using nanocarriers decreases the side effects. Nanotechnology has had a great contribution in developing Drug Delivery Systems (DDS). These DDS could function as reservoirs for sustained drug release or control the pharmacokinetics and biodistribution of the drugs. In the current review, we have collected 38 original research articles using nanotechnology as DDS for the clinically used cholinesterase inhibitor drugs donepezil (DPZ), Rivastigmine (Riv), and galantamine (Gal) used for AD treatment from 2002 to 2017 from Scopus and PubMed databases. Regarding DDS used for DPZ, most of the research in recent years dealt with polymeric nanoparticles (NPs) including Poly-D, L-Lactide-Co-Glycolide (PLGA), and chitosans (CHs), then Liposomes (LPs), nanogels, and natural products, respectively. In terms of Riv most of the research performed was focused on polymeric NPs including PLGA, polylactic acid (PLA), Poly-Ε-Caprolactone (PCL), poly-alkyl-cyanoacrylates, CH, gelatin and then LPs. The highest application of NPs in regard to Gal was related to modified LPs and polymeric NPs. Polymeric NPs demonstrate safety, higher stability in biological fluids and against enzymatic metabolism, biocompatibility, bioavailability, and improved encapsulation efficacy. LPs, another major delivery system used, demonstrate biocompatibility, ease of surface modification, and amphiphilic nature.

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Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

Nature Communications ◽

10.1038/s41467-021-22301-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Xin Ding ◽

Jin Wang ◽

Miaoxin Huang ◽

Zhangpeng Chen ◽

Jing Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Knock Out ◽

Classical Complement Pathway ◽

Synaptic Remodeling ◽

The Central Nervous System ◽

System Activation ◽

Knock Out Mice ◽

Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

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New advances in brain-targeting nano-drug delivery systems for Alzheimer's disease

Journal of Drug Targeting ◽

10.1080/1061186x.2021.1927055 ◽

2021 ◽

pp. 1-67

Author(s):

Qin Ouyang ◽

Yingcai Meng ◽

Wenhu Zhou ◽

Jianbin Tong ◽

Zeneng Cheng ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Drug Delivery ◽

Alzheimer's Disease ◽

Drug Delivery Systems ◽

Delivery Systems ◽

Brain Targeting ◽

Nano Drug Delivery

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Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Biomolecules ◽

10.3390/biom11070980 ◽

2021 ◽

Vol 11 (7) ◽

pp. 980

Author(s):

Ka-Young Kim ◽

Ki-Young Shin ◽

Keun-A. Chang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Web Of Science ◽

Meta Analysis ◽

Cochrane Library ◽

Blood Biomarkers ◽

Cell Lineages ◽

The Central Nervous System ◽

New Biomarkers ◽

T Tau

Alzheimer’s disease (AD), a progressive neurodegenerative disease, affects approximately 50 million people worldwide, which warrants the search for reliable new biomarkers for early diagnosis of AD. Brain-derived exosomal (BDE) proteins, which are extracellular nanovesicles released by all cell lineages of the central nervous system, have been focused as biomarkers for diagnosis, screening, prognosis prediction, and monitoring in AD. This review focused on the possibility of BDE proteins as AD biomarkers. The articles published prior to 26 January 2021 were searched in PubMed, EMBASE, Web of Science, and Cochrane Library to identify all relevant studies that reported exosome biomarkers in blood samples of patients with AD. From 342 articles, 20 studies were selected for analysis. We conducted a meta-analysis of six BDE proteins and found that levels of amyloid-β42 (standardized mean difference (SMD) = 1.534, 95% confidence interval [CI]: 0.595–2.474), total-tau (SMD = 1.224, 95% CI: 0.534–1.915), tau phosphorylated at threonine 181 (SMD = 4.038, 95% CI: 2.312-5.764), and tau phosphorylated at serine 396 (SMD = 2.511, 95% CI: 0.795–4.227) were significantly different in patients with AD compared to those in control. Whereas, those of p-tyrosine-insulin receptor substrate-1 and heat shock protein 70 did not show significant differences. This review suggested that Aβ42, t-tau, p-T181-tau, and p-S396-tau could be effective in diagnosing AD as blood biomarkers, despite the limitation in the meta-analysis based on the availability of data. Therefore, certain BDE proteins could be used as effective biomarkers for AD.

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