Nutraceuticals and their Derived Nano-formulations for the Prevention and Treatment of Alzheimer's disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Ashif Iqubal ◽  
Mohammad Kashif Iqubal ◽  
Syed Abul Fazal ◽  
Faheem Hyder Pottoo ◽  
Syed Ehtaishamul Haque
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Particle Size ◽  
Senile Plaques ◽  
Neurofibrillary Tangle ◽  
Hepatic Metabolism ◽  
Tau Proteins ◽  
Nitrative Stress ◽  
Effective Delivery ◽  
The Brain

: Alzheimer’s disease is one of the common chronic neurological disorders and associated with cognitive dysfunction, depression and progressive dementia. Presence of β-amyloid or senile plaques, hyper-phosphorylated tau proteins, neurofibrillary tangle, oxidative-nitrative stress, mitochondrial dysfunction, endoplasmic reticulum stress, neuroinflammation and derailed neurotransmitter status are the hallmark of AD. Currently, donepezil, memantine, rivastigmine and galantamine are approved by the FDA for symptomatic management. It is well-known that these approved drugs only exert symptomatic relief and possess poor patient-compliance. Additionally, various published evidence shows the neuroprotective potential of various nutraceuticals via their antioxidant, anti-inflammatory and anti-apoptotic effects in the preclinical and clinical studies. These nutraceuticals possess a significant neuroprotective potential and hence, can be a future pharmacotherapeutic for the management and treatment of AD. However, nutraceutical suffers from certain major limitations such as poor solubility, low bioavailability, low stability, fast hepatic-metabolism and larger particle size. These pharmacokinetic attributes restrict their entry into the brain via the blood-brain barrier. Therefore, to over such issues, various nanoformulation of nutraceuticals was developed, that allows their effective delivery into brain owning to reduced particle size, increased lipophilicity increased bioavailability and avoidance of fast hepatic metabolism. Thus, in this review, we have discussed the etiology of AD, focused on the pharmacotherapeutics of nutraceuticals with preclinical and clinical evidence, discussed pharmaceutical limitation and regulatory aspects of nutraceuticals to ensure safety and efficacy. We further explored the latitude of various nanoformulation of nutraceuticals as a novel approach to overcome the existing pharmaceutical limitation and for effective delivery into the brain.

Modulation of ϐ-amyloid production and fibrillization

2001 ◽  
Vol 67 ◽  
pp. 1-14 ◽  
Author(s):  
David Allsop ◽  
Lance J. Twyman ◽  
Yvonne Davies ◽  
Susan Moore ◽  
Amber York ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Fibrils ◽  
Senile Plaques ◽  
Neurofibrillary Tangle ◽  
Neuronal Loss ◽  
Brain Parenchyma ◽  
Amino Acid Peptide ◽  
Close Relatives ◽  
The Brain

Alzheimer's disease (AD) is the most common cause of dementia in old age and presently affects an estimated 4 million people in the U.S.A. and 0.75 million people in the U.K. It is a relentless, degenerative brain disease, characterized by progressive cognitive impairment. In the final stages of the disease, patients are often bedridden, doubly incontinent and unable to speak or to recognize close relatives. Pathological changes of Alzheimer's disease include extensive neuronal loss and the presence of numerous neurofibrillary tangles and senile plaques in the brain. The senile plaques contain amyloid fibrils derived from a 39-43-amino-acid peptide referred to as ϐ-amyloid or Aϐ. The basic theory of the so-called 'amyloid hypothesis' is that the deposition of aggregated forms of Aϐ in the brain parenchyma triggers a pathological cascade of events that leads to neurofibrillary tangle formation, neuronal loss and the associated dementia [1]. Here we discuss progress towards the identification of inhibitors of Aϐ production and fibrillization.

Fractal Dimension of the EEG in Alzheimer's Disease

2008 ◽  
pp. 603-609 ◽  
Author(s):  
Daniel Abásolo ◽  
Javier Escudero ◽  
Roberto Hornero ◽  
Pedro Espino ◽  
Carlos Gómez
Keyword(s):  
Magnetic Resonance Imaging ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Diagnosis ◽  
Senile Plaques ◽  
Cortical Atrophy ◽  
Definite Diagnosis ◽  
Histological Changes ◽  
Brain Scans ◽  
The Brain

Alzheimer’s disease (AD) is the most frequent cause of dementia in western countries, and is characterized by progressive impairments in cognition and memory, whose course lasts several years prior to death (Jeong, 2004). These clinical features are accompanied by histological changes in the brain, which include widespread cortical atrophy, intracellular deposition of neurofibrillary tangles, and extracellular deposition of senile plaques, particularly in the hippocampus and the cerebral cortex. Although a definite diagnosis is only possible by necropsy, a differential diagnosis with other types of dementia and with major depression should be attempted. Magnetic resonance imaging and computerized tomography can be normal in the early stages of AD, but a diffuse cortical atrophy is the main sign in brain scans. Mental status tests are also useful.

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

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.

scholarly journals Molecular Insight into the Therapeutic Promise of Flavonoids against Alzheimer’s Disease

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1267 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Kamal Niaz ◽  
Philippe Jeandet ◽  
Christophe Clément ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Senile Plaques ◽  
Symptomatic Relief ◽  
Point Of View ◽  
Tau Proteins ◽  
Experimental Proof ◽  
Aβ Peptides ◽  
Inhibitory Potential

Alzheimer’s disease (AD) is one of the utmost chronic neurodegenerative disorders, which is characterized from a neuropathological point of view by the aggregates of amyloid beta (Aβ) peptides that are deposited as senile plaques and tau proteins which form neurofibrillary tangles (NFTs). Even though advancement has been observed in order to understand AD pathogenesis, currently available therapeutic methods can only deliver modest symptomatic relief. Interestingly, naturally occurring dietary flavonoids have gained substantial attention due to their antioxidative, anti-inflammatory, and anti-amyloidogenic properties as alternative candidates for AD therapy. Experimental proof provides support to the idea that some flavonoids might protect AD by interfering with the production and aggregation of Aβ peptides and/or decreasing the aggregation of tau. Flavonoids have the ability to promote clearance of Aβ peptides and inhibit tau phosphorylation by the mTOR/autophagy signaling pathway. Moreover, due to their cholinesterase inhibitory potential, flavonoids can represent promising symptomatic anti-Alzheimer agents. Several processes have been suggested for the aptitude of flavonoids to slow down the advancement or to avert the onset of Alzheimer’s pathogenesis. To enhance cognitive performance and to prevent the onset and progress of AD, the interaction of flavonoids with various signaling pathways is proposed to exert their therapeutic potential. Therefore, this review elaborates on the probable therapeutic approaches of flavonoids aimed at averting or slowing the progression of the AD pathogenesis.

scholarly journals Neuron loss associated with age but not Alzheimer's disease pathology in the chimpanzee brain

2020 ◽  
Vol 375 (1811) ◽  
pp. 20190619 ◽  
Author(s):  
Melissa K. Edler ◽  
Emily L. Munger ◽  
Richard S. Meindl ◽  
William D. Hopkins ◽  
John J. Ely ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangle ◽  
Cell Loss ◽  
Tau Proteins ◽  
Middle Temporal Gyrus ◽  
Neuron Death ◽  
Neuron Loss ◽  
Neuron Density ◽  
Age Related

In the absence of disease, ageing in the human brain is accompanied by mild cognitive dysfunction, gradual volumetric atrophy, a lack of significant cell loss, moderate neuroinflammation, and an increase in the amyloid beta (A β ) and tau proteins. Conversely, pathologic age-related conditions, particularly Alzheimer's disease (AD), result in extensive neocortical and hippocampal atrophy, neuron death, substantial A β plaque and tau-associated neurofibrillary tangle pathologies, glial activation and severe cognitive decline. Humans are considered uniquely susceptible to neurodegenerative disorders, although recent studies have revealed A β and tau pathology in non-human primate brains. Here, we investigate the effect of age and AD-like pathology on cell density in a large sample of postmortem chimpanzee brains ( n = 28, ages 12–62 years). Using a stereologic, unbiased design, we quantified neuron density, glia density and glia:neuron ratio in the dorsolateral prefrontal cortex, middle temporal gyrus, and CA1 and CA3 hippocampal subfields. Ageing was associated with decreased CA1 and CA3 neuron densities, while AD pathologies were not correlated with changes in neuron or glia densities. Differing from cerebral ageing and AD in humans, these data indicate that chimpanzees exhibit regional neuron loss with ageing but appear protected from the severe cell death found in AD. This article is part of the theme issue ‘Evolution of the primate ageing process’.

scholarly journals Fibrillogenesis in Alzheimer's disease of amyloid β peptides and apolipoprotein E

1995 ◽  
Vol 306 (2) ◽  
pp. 599-604 ◽  
Author(s):  
E M Castano ◽  
F Prelli ◽  
T Wisniewski ◽  
A Golabek ◽  
R A Kumar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Tau Proteins ◽  
Amyloid Formation

A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.

scholarly journals Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer’s disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shan-Shan Wang ◽  
Zi-Kai Liu ◽  
Jing-Jing Liu ◽  
Qing Cheng ◽  
Yan-Xia Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Senile Plaques ◽  
Disease Stage ◽  
Assay Method ◽  
Imaging Probe ◽  
Asparaginyl Endopeptidase ◽  
Potential Biomarker ◽  
The Brain

Abstract Background Discovery of early-stage biomarkers is a long-sought goal of Alzheimer’s disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn’t proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology. Results This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala–Ala–Asn–Cys–Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg−1, p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice. Conclusions The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD. Graphical abstract

scholarly journals Editorial for the Genetics of Alzheimer’s Disease Special Issue: October 2021

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1794
Author(s):  
Laura Ibanez ◽  
Justin B. Miller
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gray Matter ◽  
Neuronal Death ◽  
Tau Proteins ◽  
Special Issue ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Brain

Alzheimer’s disease is a complex and multifactorial condition regulated by both genetics and lifestyle, which ultimately results in the accumulation of β-amyloid (Aβ) and tau proteins in the brain, loss of gray matter, and neuronal death [...]

scholarly journals Effect of Vitamin D Supplementation on the Progression of Alzheimer’s Disease in Rats: A Mechanistic Approach

2021 ◽  
Author(s):  
Parmi Patel ◽  
Jigna Samir Shah
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vitamin D ◽  
Vitamin D Supplementation ◽  
Cognitive Status ◽  
Tau Proteins ◽  
Biochemical Alterations ◽  
Vitamin D Levels ◽  
The Brain

Abstract Purpose: A multifaceted treatment approach can be effective for Alzheimer's disease (AD). However, currently, it involves only symptomatic treatment with cholinergic drugs. Beneficial effects of high vitamin D levels or its intake in the prevention and treatment of cognitive disorders have been reported. Thus, the present study examined the preventive effect of vitamin D supplementation on AD progression and evaluated its impact on the accumulation or degradation of Aβ plaques. Methods: A single intraperitoneal injection of scopolamine was used to induce AD in rats. Treatment of vitamin D was provided for 21 days after the injection. Various behavioral parameters like learning, spatial memory and exploratory behavior, biochemical alterations in the brain homogenate and histology of the hippocampus were investigated. Results: Our results indicated that scopolamine-induced rats depicted cognitive deficits with high Aβ levels and hyperphosphorylated tau proteins in the brain tissue, while vitamin D supplementation could significantly improve the cognitive status and lower these protein levels. These results were supported by the histopathological and immunohistochemical staining of the hippocampal brain region. Furthermore, mechanistic analysis depicted that vitamin D supplementation improved the Aβ protein clearance by increasing the neprilysin levels. It also reduced the accumulation of Aβ plaques by lowering neuroinflammation as well as oxidative stress. Conclusion: The present findings indicate that vitamin D supplementation can delay AD progression by an increase in Aβ plaques degradation or reducing inflammation and oxidative stress.

Does Diabetes Protect or Provoke Alzheimer's Disease? Insights Into the Pathobiology and Future Treatment of Alzheimer's Disease

CNS Spectrums ◽  
2003 ◽  
Vol 8 (11) ◽  
pp. 815-822 ◽  
Author(s):  
Hillel Grossman
Keyword(s):  
Diabetes Mellitus ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangle ◽  
Insulin Degrading Enzyme ◽  
Future Treatment ◽  
Epidemiologic Evidence ◽  
Insulin Dysregulation ◽  
Glycation End Products ◽  
The Brain

ABSTRACTDiabetes mellitus has long been considered a risk factor for the development of vascular dementia. Epidemiologic evidence has suggested that diabetes mellitus significantly increases risk for the development of Alzheimer's disease, independent of vascular risk factors. As insulin's role as a neuromodulator in the brain has been described, its significance for AD has also emerged. Insulin dysregulation may contribute to AD pathology through several mechanisms including decreased cortical glucose utilization particularly in the hippocampus and entorhinal cortex; increased oxidative stress through the formation of advanced glycation end-products; increased Tau phosphorylation and neurofibrillary tangle formation; increased β-amyloid aggregation through inhibition of insulin-degrading enzyme. Future treatment of AD might involve pharmacologic and dietary manipulations of insulin and glucose regulation.

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