Role of Nanomedicines in Delivery of Anti-Acetylcholinesterase Compounds to the Brain in Alzheimer’s Disease

Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by progressive neuron losses in memory-related brain structures. The classical features of AD are a dysregulation of the cholinergic system, the accumulation of amyloid plaques, and neurofibrillary tangles. Unfortunately, current treatments are unable to cure or even delay the progression of the disease. Therefore, new therapeutic strategies have emerged, such as the exogenous administration of neurotrophic factors (e.g., NGF and BDNF) that are deficient or dysregulated in AD. However, their low capacity to cross the blood–brain barrier and their exorbitant cost currently limit their use. To overcome these limitations, short peptides mimicking the binding receptor sites of these growth factors have been developed. Such peptides can target selective signaling pathways involved in neuron survival, differentiation, and/or maintenance. This review focuses on growth factors and their derived peptides as potential treatment for AD. It describes (1) the physiological functions of growth factors in the brain, their neuronal signaling pathways, and alteration in AD; (2) the strategies to develop peptides derived from growth factor and their capacity to mimic the role of native proteins; and (3) new advancements and potential in using these molecules as therapeutic treatments for AD, as well as their limitations.

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Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

International Journal of Molecular Sciences ◽

10.3390/ijms22073330 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3330

Author(s):

Mehdi Eshraghi ◽

Aida Adlimoghaddam ◽

Amir Mahmoodzadeh ◽

Farzaneh Sharifzad ◽

Hamed Yasavoli-Sharahi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Target ◽

Neurological Disorder ◽

Inflammatory Cells ◽

Disease Pathogenesis ◽

Current Review ◽

The Brain ◽

Comprehensive Discussion

Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including am-yloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.

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Neuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease

Current Neuropharmacology ◽

10.2174/1570159x19666210826130210 ◽

2021 ◽

Vol 19 ◽

Author(s):

Md. Sahab Uddin ◽

Md. Tanvir Kabir ◽

Maroua Jalouli ◽

Md. Ataur Rahman ◽

Philippe Jeandet ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Innate Immune ◽

Misfolded Proteins ◽

Inflammatory Signaling ◽

Genome Wide Analysis ◽

Genome Wide ◽

Immunological Mechanisms ◽

The Brain

: Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the formation of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques. Growing evidence has suggested that AD pathogenesis is not only limited to the neuronal compartment but also strongly interacts with immunological processes in the brain. On the other hand, aggregated and misfolded proteins can bind with pattern recognition receptors located on astroglia and microglia and can in turn induce an innate immune response, characterized by the release of inflammatory mediators, ultimately playing a role in both the severity and the progression of the disease. It has been reported by genome-wide analysis that several genes which elevate the risk for sporadic AD encode for factors controlling the inflammatory response and glial clearance of misfolded proteins. Obesity and systemic inflammation are examples of external factors which may interfere with the immunological mechanisms of the brain and can induce disease progression. In this review, we discussed the mechanisms and essential role of inflammatory signaling pathways in AD pathogenesis. Indeed, interfering with immune processes and modulation of risk factors may lead to future therapeutic or preventive AD approaches.

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The Role of Long Noncoding RNAs in Diabetic Alzheimer’s Disease

Journal of Clinical Medicine ◽

10.3390/jcm7110461 ◽

2018 ◽

Vol 7 (11) ◽

pp. 461 ◽

Cited By ~ 4

Author(s):

Young-Kook Kim ◽

Juhyun Song

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Glucose Dysregulation ◽

Near Future ◽

The Brain

Long noncoding RNAs (lncRNAs) are involved in diverse physiological and pathological processes by modulating gene expression. They have been found to be dysregulated in the brain and cerebrospinal fluid of patients with neurodegenerative diseases, and are considered promising therapeutic targets for treatment. Among the various neurodegenerative diseases, diabetic Alzheimer’s disease (AD) has been recently emerging as an important issue due to several unexpected reports suggesting that metabolic issues in the brain, such as insulin resistance and glucose dysregulation, could be important risk factors for AD. To facilitate understanding of the role of lncRNAs in this field, here we review recent studies on lncRNAs in AD and diabetes, and summarize them with different categories associated with the pathogenesis of the diseases including neurogenesis, synaptic dysfunction, amyloid beta accumulation, neuroinflammation, insulin resistance, and glucose dysregulation. It is essential to understand the role of lncRNAs in the pathogenesis of diabetic AD from various perspectives for therapeutic utilization of lncRNAs in the near future.

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Sex Differences and the Influence of Sex Hormones on Cognition through Adulthood and the Aging Process

Brain Sciences ◽

10.3390/brainsci8090163 ◽

2018 ◽

Vol 8 (9) ◽

pp. 163 ◽

Cited By ~ 17

Author(s):

Caroline Gurvich ◽

Kate Hoy ◽

Natalie Thomas ◽

Jayashri Kulkarni

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Sex Differences ◽

Cognitive Functioning ◽

Sex Hormones ◽

Reproductive Function ◽

Health And Disease ◽

And Function ◽

The Brain

Hormones of the hypothalamic-pituitary-gonadal (HPG) axis that regulate reproductive function have multiple effects on the development, maintenance and function of the brain. Sex differences in cognitive functioning have been reported in both health and disease, which may be partly attributed to sex hormones. The aim of the current paper was to provide a theoretical review of how sex hormones influence cognitive functioning across the lifespan as well as provide an overview of the literature on sex differences and the role of sex hormones in cognitive decline, specifically in relation to Alzheimer’s disease (AD). A summary of current hormone and sex-based interventions for enhancing cognitive functioning and/or reducing the risk of Alzheimer’s disease is also provided.

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Genetic Variants of Lipoprotein Lipase and Regulatory Factors Associated with Alzheimer’s Disease Risk

International Journal of Molecular Sciences ◽

10.3390/ijms21218338 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8338

Author(s):

Kimberley D. Bruce ◽

Maoping Tang ◽

Philip Reigan ◽

Robert H. Eckel

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lipoprotein Lipase ◽

Genetic Variants ◽

Disease Risk ◽

Lipoprotein Metabolism ◽

Protective Role ◽

Direct Role ◽

The Brain

Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer’s disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, HindIII, and PvuII) have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis.

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Activate or Inhibit? Implications of Autophagy Modulation as a Therapeutic Strategy for Alzheimer’s Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21186739 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6739

Author(s):

Sharmeelavathi Krishnan ◽

Yasaswi Shrestha ◽

Dona P. W. Jayatunga ◽

Sarah Rea ◽

Ralph Martins ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Therapeutic Strategy ◽

Senile Plaques ◽

Physiological State ◽

Proteotoxic Stress ◽

Underlying Causes ◽

The Brain

Neurodegenerative diseases result in a range of conditions depending on the type of proteinopathy, genes affected or the location of the degeneration in the brain. Proteinopathies such as senile plaques and neurofibrillary tangles in the brain are prominent features of Alzheimer’s disease (AD). Autophagy is a highly regulated mechanism of eliminating dysfunctional organelles and proteins, and plays an important role in removing these pathogenic intracellular protein aggregates, not only in AD, but also in other neurodegenerative diseases. Activating autophagy is gaining interest as a potential therapeutic strategy for chronic diseases featuring protein aggregation and misfolding, including AD. Although autophagy activation is a promising intervention, over-activation of autophagy in neurodegenerative diseases that display impaired lysosomal clearance may accelerate pathology, suggesting that the success of any autophagy-based intervention is dependent on lysosomal clearance being functional. Additionally, the effects of autophagy activation may vary significantly depending on the physiological state of the cell, especially during proteotoxic stress and ageing. Growing evidence seems to favour a strategy of enhancing the efficacy of autophagy by preventing or reversing the impairments of the specific processes that are disrupted. Therefore, it is essential to understand the underlying causes of the autophagy defect in different neurodegenerative diseases to explore possible therapeutic approaches. This review will focus on the role of autophagy during stress and ageing, consequences that are linked to its activation and caveats in modulating this pathway as a treatment.

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Recent progress on the role of GABAergic neurotransmission in the pathogenesis of Alzheimer’s disease

Reviews in the Neurosciences ◽

10.1515/revneuro-2015-0062 ◽

2016 ◽

Vol 27 (4) ◽

pp. 449-455 ◽

Cited By ~ 3

Author(s):

Ghulam Abbas ◽

Wajahat Mahmood ◽

Nurul Kabir

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gaba Receptor ◽

Amyloid Β ◽

Receptor Subtypes ◽

Causative Role ◽

Gabaergic Neurotransmission ◽

Promising Target ◽

The Brain

AbstractDespite their possible causative role, targeting amyloidosis, tau phosphorylation, acetylcholine esterase, glutamate, oxidative stress and mitochondrial metabolism have not yet led to the development of drugs to cure Alzheimer’s disease (AD). Recent preclinical and clinical reports exhibit a surge in interest in the role of GABAergic neurotransmission in the pathogenesis of AD. The interaction among GABAergic signaling, amyloid-β and acetylcholine is shown to affect the homeostasis between excitation (glutamate) and inhibition (GABA) in the brain. As a consequence, over-excitation leads to neurodegeneration (excitotoxicity) and impairment in the higher level functions. Previously, the glutamate arm of this balance received the most attention. Recent literature suggests that over-excitation is primarily mediated by dysfunctional GABA signaling and can possibly be restored by rectifying anomalous metabolism observed in the GABAergic neurons during AD. Additionally, neurogenesis and synaptogenesis have also been linked with GABAergic signaling. This association may provide a basis for the needed repair mechanism. Furthermore, several preclinical interventional studies revealed that targeting various GABA receptor subtypes holds potential in overcoming the memory deficits associated with AD. In conclusion, the recent scientific literature suggests that GABAergic signaling presents itself as a promising target for anti-AD drug development.

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Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21228767 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8767

Author(s):

Nicole Jacqueline Jensen ◽

Helena Zander Wodschow ◽

Malin Nilsson ◽

Jørgen Rungby

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurodegenerative Diseases ◽

Brain Metabolism ◽

Ketone Bodies ◽

Current Knowledge ◽

Ketogenic Diets ◽

Cognitive Benefits ◽

The Brain

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

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TRANSGENIC MOUSE MODELS OF ALZHEIMER’S DISEASE

Innovation in Aging ◽

10.1093/geroni/igz038.3077 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S835-S835

Author(s):

Charnae A Henry-Smith ◽

Xianlin Han

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Myelin Sheath ◽

Thinking Skills ◽

Drug Dosage ◽

Whole Body ◽

To Receive ◽

The Brain

Abstract Alzheimer’s disease is a progressive brain disease that slowly destroys memory and thinking skills. Alzheimer’s is characterized by an increase in Aβ plaques , and tau tangles. Neurons in the brain have axons covered in myelin sheath that connect microglia and astrocytes. The myelin sheath is composed of about 70% lipid composition; Sulfatide contributing to 30% overall. Sulfatide changes the morphology of primary microglia to their activated form. To study the role of microglia activation and sulfatide levels, three different mouse models were created: APP KI mice, CST Whole Body Ko mice, and cCST (conditional) KO. In order to create the genotype of the APP KI mice, a breeding mouse line was created. The APP KI gene had to be introduced in Plp1-Cre and cCST KO crossed mice to receive a working mouse model. During the duration of breeding for the APP KI mice, a preliminary experiment was performed on the CST KO mice. These mice were given the PLX3397 diet with the aim to remove the microglia and to see the effect of Aβ plaques. The PLX3397 will reduce the microglia targeting the CSF1R. After consuming the diet, the mice were harvested to collect tissues from the brain and spinal cord. Lipidomics and immunohistology were performed. In conclusion, we will continue the breeding of the CST flox/flox / Plp1-Cre / APP KI mice, and the drug dosage and treatment to be used in our APP KI mice will be based on preliminary data from our CST mice.

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