Effects of curcumin and demethoxycurcumin on amyloid-β precursor and tau proteins through the internal ribosome entry sites: A potential therapeutic for Alzheimer's disease

Abstract Alzheimer’s disease (AD), the most common cause of dementia, is characterized by progressive cognitive and memory impairment ensued from neuronal dysfunction and eventual death. Intraneuronal deposition of tau proteins and extracellular senile amyloid-β plaques have ruled as the supreme postulations of AD for a relatively long time, and accordingly, a wide range of therapeutics, especially immunotherapies have been implemented. However, none of them resulted in significant positive cognitive outcomes. Especially, the repetitive failure of anti-amyloid therapies proves the inefficiency of the amyloid cascade hypothesis, suggesting that it is time to reconsider this hypothesis. Thus, for the time being, the focus is being shifted to neuroinflammation as a third core pathology in AD. Neuroinflammation was previously considered a result of the two aforementioned phenomena, but new studies suggest that it might play a causal role in the pathogenesis of AD. Neuroinflammation can act as a double-edged sword in the pathogenesis of AD, and the activation of glial cells is indispensable for mediating such attenuating or detrimental effects. The association of immune-related genes polymorphisms with the clinical phenotype of AD as well as the protective effect of anti-inflammatory drugs like nonsteroidal anti-inflammatory drugs supports the possible causal role of neuroinflammation in AD. Here, we comprehensively review immune-based therapeutic approaches toward AD, including monoclonal antibodies and vaccines. We also discuss their efficacy and underlying reasons for shortcomings. Lastly, we highlight the capacity of modulating the neuroimmune interactions and targeting neuroinflammation as a promising opportunity for finding optimal treatments for AD.

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Poor Diet, Stress, and Inactivity Converge to Form a “Perfect Storm” That Drives Alzheimer’s Disease Pathogenesis

Neurodegenerative Diseases ◽

10.1159/000503451 ◽

2019 ◽

Vol 19 (2) ◽

pp. 60-77 ◽

Cited By ~ 2

Author(s):

Anthony G. Pacholko ◽

Caitlin A. Wotton ◽

Lane K. Bekar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Environmental Factors ◽

Late Onset ◽

Caloric Intake ◽

Amyloid Β ◽

Tau Proteins ◽

Loss Of Function ◽

Brain Insulin Resistance ◽

Perfect Storm

North American incidence of Alzheimer’s disease (AD) is expected to more than double over the coming generation. Although genetic factors surrounding the production and clearance of amyloid-β and phosphorylated tau proteins are known to be responsible for a subset of early-onset AD cases, they do not explain the pathogenesis of the far more prevalent sporadic late-onset variant of the disease. It is thus likely that lifestyle and environmental factors contribute to neurodegenerative processes implicated in the pathogenesis of AD. Herein, we review evidence that (1) excess sucrose consumption induces AD-associated liver pathologies and brain insulin resistance, (2) chronic stress overdrives activity of locus coeruleus neurons, leading to loss of function (a common event in neurodegeneration), (3) high-sugar diets and stress promote the loss of neuroprotective sex hormones in men and women, and (4) Western dietary trends set the stage for a lithium-deficient state. We propose that these factors may intersect as part of a “perfect storm” to contribute to the widespread prevalence of neurodegeneration and AD. In addition, we put forth the argument that exercise and supplementation with trace lithium can counteract many of the deleterious consequences associated with excessive caloric intake and perpetual stress. We conclude that lifestyle and environmental factors likely contribute to AD pathogenesis and that simple lifestyle and dietary changes can help counteract their effects.

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

Biochemical Journal ◽

10.1042/bj3060599 ◽

1995 ◽

Vol 306 (2) ◽

pp. 599-604 ◽

Cited By ~ 152

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.

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The coupling of global brain activity and cerebrospinal fluid inflow is correlated with Alzheimer’s disease related pathology

10.1101/2020.06.04.134726 ◽

2020 ◽

Author(s):

Feng Han ◽

Jing Chen ◽

Aaron Belkin-Rosen ◽

Yameng Gu ◽

Liying Luo ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Driving Forces ◽

Brain Activity ◽

Amyloid Β ◽

Resting State Fmri ◽

High Amplitude ◽

Tau Proteins ◽

Global Brain

AbstractThe glymphatic system plays an important role in clearing the amyloid-β and tau proteins that are closely linked to Alzheimer’s disease (AD) pathology. Glymphatic clearance, as well as amyloid-β accumulation, is highly dependent on sleep, but the sleep-dependent driving forces behind cerebrospinal fluid (CSF) movements essential to the glymphatic flux remain largely unclear. Recent studies have reported that widespread, high-amplitude spontaneous brain activations in the drowsy state and during sleep, which are shown as large global signal peaks in resting-state fMRI, is coupled with the CSF movements, suggesting their potential link to the glymphatic flux and metabolite clearance. By analyzing multimodal data from the Alzheimer’s Disease Neuroimaging Initiative project, here we showed that the coupling between the global fMRI signal and CSF influx is correlated with AD-related pathology, including various risk factors for AD, the severity of AD-related diseases, the cortical amyloid-β level, and the cognitive decline over a two-year follow-up. These results provide critical initial evidence for involvement of sleep-dependent global brain activity, as well as the associated physiological modulations, in the clearance of AD-related brain waste.

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Alzheimer’s disease: many failed trials, so where do we go from here?

Journal of Investigative Medicine ◽

10.1136/jim-2020-001297 ◽

2020 ◽

Vol 68 (6) ◽

pp. 1135-1140 ◽

Cited By ~ 1

Author(s):

Allison Bethanne Reiss ◽

Amy D Glass ◽

Thomas Wisniewski ◽

Benjamin Wolozin ◽

Irving H Gomolin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Current Knowledge ◽

Memory Loss ◽

Treatment Strategies ◽

Amyloid Β ◽

Tau Proteins ◽

Brain Disorder ◽

The Central Nervous System ◽

Progressive Cognitive Impairment

Alzheimer’s disease (AD) is a neurodegenerative brain disorder associated with relentlessly progressive cognitive impairment and memory loss. AD pathology proceeds for decades before cognitive deficits become clinically apparent, opening a window for preventative therapy. Imbalance of clearance and buildup of amyloid β and phosphorylated tau proteins in the central nervous system is believed to contribute to AD pathogenesis. However, multiple clinical trials of treatments aimed at averting accumulation of these proteins have yielded little success, and there is still no disease-modifying intervention. Here, we discuss current knowledge of AD pathology and treatment with an emphasis on emerging biomarkers and treatment strategies.

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Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade

Journal of Alzheimer s Disease ◽

10.3233/jad-189015 ◽

2019 ◽

Vol 68 (1) ◽

pp. 415-415 ◽

Cited By ~ 1

Author(s):

Walter Gulisano ◽

Daniele Maugeri ◽

Marian A. Baltrons ◽

Mauro Fà ◽

Arianna Amato ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Tau Proteins ◽

Amyloid Cascade

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Anti-Neuroinflammatory Potential of Polyphenols by Inhibiting NF-κB to Halt Alzheimer's Disease

Current Pharmaceutical Design ◽

10.2174/1381612826666201118092422 ◽

2020 ◽

Vol 26 ◽

Author(s):

Md. Sahab Uddin ◽

Sharifa Hasana ◽

Jamil Ahmad ◽

Md. Farhad Hossain ◽

Md. Mosiqur Rahman ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Amyloid Β ◽

Neuronal Loss ◽

Research Area ◽

Tau Proteins ◽

Brain Disorder ◽

Drug Candidates ◽

Life Threatening

: Alzheimer's disease (AD) is an irrevocable chronic brain disorder featured by neuronal loss, microglial accumulation, and progressive cognitive impairment. The proper pathophysiology of this life-threatening disorder is not completely understood and no exact remedies are found yet. Over the last few decades, research on AD has mainly highlighted in pathomechanisms linked to a couple of the major pathological hallmarks, including extracellular senile plaques, made of amyloid-β (Aβ) peptides, and intracellular neurofibrillary tangles (NFTs), made of tau proteins. Aβ can induce apoptosis, trigger an inflammatory response, and inhibit the synaptic plasticity of the hippocampus, which ultimately contributes to reducing cognitive functions and memory impairment. Recently, a third disease hallmark, the neuroinflammatory reaction that is mediated by cerebral innate immune cells, has become a spotlight in the current research area, assured by pre-clinical, clinical, and genetic investigations. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a cytokine producer, is significantly associated with physiological inflammatory proceedings and thus showing a promising candidate for inflammation-based AD therapy. Recent data reveal that phytochemicals mainly polyphenols compounds exhibit potential neuroprotective functions and it may be considered as a vital resource for discovering several drug candidates against AD. Interestingly, phytochemicals can easily interfere with the signaling pathway of NF-κB. This review represents the anti-neuroinflammatory potential of polyphenols as inhibitors of NF-κB to combat AD pathogenesis.

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Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade

Journal of Alzheimer s Disease ◽

10.3233/jad-179935 ◽

2018 ◽

Vol 64 (s1) ◽

pp. S611-S631 ◽

Cited By ~ 23

Author(s):

Walter Gulisano ◽

Daniele Maugeri ◽

Marian A. Baltrons ◽

Mauro Fà ◽

Arianna Amato ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Tau Proteins ◽

Amyloid Cascade

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Neuron-specific methylome analysis reveals epigenetic regulation and tau-related dysfunction of BRCA1 in Alzheimer’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707151114 ◽

2017 ◽

Vol 114 (45) ◽

pp. E9645-E9654 ◽

Cited By ~ 36

Author(s):

Tatsuo Mano ◽

Kenichi Nagata ◽

Takashi Nonaka ◽

Airi Tarutani ◽

Tomohiro Imamura ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Tau Proteins ◽

Epigenetic Mechanism ◽

Dependent Manner ◽

Brca1 Protein ◽

Dna Methylome ◽

Methylome Analysis ◽

The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

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