Neuropeptides in Alzheimer’s Disease: An Update

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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Potential Role of Phenolic Extracts of Mentha in Managing Oxidative Stress and Alzheimer’s Disease

Antioxidants ◽

10.3390/antiox9070631 ◽

2020 ◽

Vol 9 (7) ◽

pp. 631

Author(s):

Doaa M. Hanafy ◽

Geoffrey E. Burrows ◽

Paul D. Prenzler ◽

Rodney A. Hill

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Potential Role ◽

The Elderly ◽

Future Research ◽

Phenolic Constituents ◽

The Central Nervous System ◽

Developed Nations

With an increase in the longevity and thus the proportion of the elderly, especially in developed nations, there is a rise in pathological conditions that accompany ageing, such as neurodegenerative disorders. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive and memory decline. The pathophysiology of the disease is poorly understood, with several factors contributing to its development, such as oxidative stress, neuroinflammation, cholinergic neuronal apoptotic death, and the accumulation of abnormal proteins in the brain. Current medications are only palliative and cannot stop or reverse the progression of the disease. Recent clinical trials of synthetic compounds for the treatment of AD have failed because of their adverse effects or lack of efficacy. Thus, there is impetus behind the search for drugs from natural origins, in addition to the discovery of novel, conventional therapeutics. Mints have been used traditionally for conditions relevant to the central nervous system. Recent studies showed that mint extracts and/or their phenolic constituents have a neuroprotective potential and can target multiple events of AD. In this review, we provide evidence of the potential role of mint extracts and their derivatives as possible sources of treatments in managing AD. Some of the molecular pathways implicated in the development of AD are reviewed, with focus on apoptosis and some redox pathways, pointing to mechanisms that may be modulated for the treatment of AD, and the need for future research invoking knowledge of these pathways is highlighted.

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Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review

Cells ◽

10.3390/cells10051138 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1138

Author(s):

Melissa K. Edler ◽

Isha Mhatre-Winters ◽

Jason R. Richardson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Single Species ◽

Functional Behavior ◽

Age Related ◽

Rapid Changes ◽

The Central Nervous System ◽

Oxidative Species ◽

Selection Of

Microglia are the primary immune cells of the central nervous system that help nourish and support neurons, clear debris, and respond to foreign stimuli. Greatly impacted by their environment, microglia go through rapid changes in cell shape, gene expression, and functional behavior during states of infection, trauma, and neurodegeneration. Aging also has a profound effect on microglia, leading to chronic inflammation and an increase in the brain’s susceptibility to neurodegenerative processes that occur in Alzheimer’s disease. Despite the scientific community’s growing knowledge in the field of neuroinflammation, the overall success rate of drug treatment for age-related and neurodegenerative diseases remains incredibly low. Potential reasons for the lack of translation from animal models to the clinic include the use of a single species model, an assumption of similarity in humans, and ignoring contradictory data or information from other species. To aid in the selection of validated and predictive animal models and to bridge the translational gap, this review evaluates similarities and differences among species in microglial activation and density, morphology and phenotype, cytokine expression, phagocytosis, and production of oxidative species in aging and Alzheimer’s disease.

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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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Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems

Current Drug Targets ◽

10.2174/1389450120666191118123151 ◽

2020 ◽

Vol 21 (7) ◽

pp. 628-646

Author(s):

Gülcem Altinoglu ◽

Terin Adali

Keyword(s):

Alzheimer’S Disease ◽

Drug Delivery ◽

Alzheimer's Disease ◽

Neurological Diseases ◽

Sustained Drug Release ◽

Physiochemical Properties ◽

Conventional Drug ◽

Health Care Burden ◽

The Central Nervous System ◽

Effective Drugs

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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Consideration of a Pharmacological Combinatorial Approach to Inhibit Chronic Inflammation in Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205016666191106095038 ◽

2019 ◽

Vol 16 (11) ◽

pp. 1007-1017 ◽

Cited By ~ 1

Author(s):

James G. McLarnon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Models ◽

Chronic Inflammation ◽

Preventive Strategy ◽

Subsequent Work ◽

Activated Microglia ◽

Starting Point ◽

Anti Inflammatory ◽

Cocktail Approach

A combinatorial cocktail approach is suggested as a rationale intervention to attenuate chronic inflammation and confer neuroprotection in Alzheimer’s disease (AD). The requirement for an assemblage of pharmacological compounds follows from the host of pro-inflammatory pathways and mechanisms present in activated microglia in the disease process. This article suggests a starting point using four compounds which present some differential in anti-inflammatory targets and actions but a commonality in showing a finite permeability through Blood-brain Barrier (BBB). A basis for firstchoice compounds demonstrated neuroprotection in animal models (thalidomide and minocycline), clinical trial data showing some slowing in the progression of pathology in AD brain (ibuprofen) and indirect evidence for putative efficacy in blocking oxidative damage and chemotactic response mediated by activated microglia (dapsone). It is emphasized that a number of candidate compounds, other than ones suggested here, could be considered as components of the cocktail approach and would be expected to be examined in subsequent work. In this case, systematic testing in AD animal models is required to rigorously examine the efficacy of first-choice compounds and replace ones showing weaker effects. This protocol represents a practical approach to optimize the reduction of microglial-mediated chronic inflammation in AD pathology. Subsequent work would incorporate the anti-inflammatory cocktail delivery as an adjunctive treatment with ones independent of inflammation as an overall preventive strategy to slow the progression of AD.

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Alzheimer's Disease Brain Areas: The Machine Learning Support for Blind Localization

Current Alzheimer Research ◽

10.2174/1567205013666160314144822 ◽

2016 ◽

Vol 13 (5) ◽

pp. 498-508 ◽

Cited By ~ 2

Author(s):

V. Vigneron ◽

A. Kodewitz ◽

A. M. Tome ◽

S. Lelandais ◽

E. Lang

Keyword(s):

Machine Learning ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Learning Support ◽

Brain Areas

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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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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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