Evaluation of heptelidic acid as a potential inhibitor for tau aggregation-induced Alzheimer's disease and associated neurotoxicity

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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Arrayed CRISPR reveals genetic regulators of tau aggregation, autophagy and mitochondria in Alzheimer’s disease model

Scientific Reports ◽

10.1038/s41598-021-82658-7 ◽

2021 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Lishu Duan ◽

Mufeng Hu ◽

Joseph A. Tamm ◽

Yelena Y. Grinberg ◽

Fang Shen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Discovery ◽

Disease Model ◽

Mitochondrial Morphology ◽

Individual Gene ◽

Human Genes ◽

Future Drug ◽

Tau Aggregation

AbstractAlzheimer’s disease (AD) is a common neurodegenerative disease with poor prognosis. New options for drug discovery targets are needed. We developed an imaging based arrayed CRISPR method to interrogate the human genome for modulation of in vitro correlates of AD features, and used this to assess 1525 human genes related to tau aggregation, autophagy and mitochondria. This work revealed (I) a network of tau aggregation modulators including the NF-κB pathway and inflammatory signaling, (II) a correlation between mitochondrial morphology, respiratory function and transcriptomics, (III) machine learning predicted novel roles of genes and pathways in autophagic processes and (IV) individual gene function inferences and interactions among biological processes via multi-feature clustering. These studies provide a platform to interrogate underexplored aspects of AD biology and offer several specific hypotheses for future drug discovery efforts.

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“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

Molecular Neurodegeneration ◽

10.1186/s13024-021-00460-5 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Yuxing Xia ◽

Stefan Prokop ◽

Benoit I. Giasson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Kinase Inhibitors ◽

Tau Phosphorylation ◽

Phosphorylated Tau ◽

Clinical Biomarkers ◽

Early Results ◽

Recent Developments ◽

Tau Aggregation

AbstractPhosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

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Alzheimer’s disease brain contains tau fractions with differential prion-like activities

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01127-4 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Longfei Li ◽

Ruirui Shi ◽

Jianlan Gu ◽

Yunn Chyn Tung ◽

Yan Zhou ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cultured Cells ◽

Regional Distribution ◽

Proteinase K ◽

Hyperphosphorylated Tau ◽

Terminal Portion ◽

Tau Pathology ◽

Heat Stable ◽

Tau Aggregation

AbstractNeurofibrillary tangles (NFTs) made of abnormally hyperphosphorylated tau are a hallmark of Alzheimer’s disease (AD) and related tauopathies. Regional distribution of NFTs is associated with the progression of the disease and has been proposed to be a result of prion-like propagation of misfolded tau. Tau in AD brain is heterogenous and presents in various forms. In the present study, we prepared different tau fractions by sedimentation combined with sarkosyl solubility from AD brains and analyzed their biochemical and pathological properties. We found that tau in oligomeric fraction (O-tau), sarkosyl-insoluble fractions 1 and 2 (SI1-tau and SI2-tau) and monomeric heat-stable fraction (HS-tau) showed differences in truncation, hyperphosphorylation, and resistance to proteinase K. O-tau, SI1-tau, and SI2-tau, but not HS-tau, were hyperphosphorylated at multiple sites and contained SDS- and β-mercaptoethanol–resistant high molecular weight aggregates, which lacked the N-terminal portion of tau. O-tau and SI2-tau displayed more truncation and less hyperphosphorylation than SI1-tau. Resistance to proteinase K was increased from O-tau to SI1-tau to SI2-tau. O-tau and SI1-tau, but not SI2-tau or HS-tau, captured tau from cell lysates and seeded tau aggregation in cultured cells. Heat treatment could not kill the prion-like activity of O-tau to capture normal tau. Hippocampal injection of O-tau into 18-month-old FVB mice induced significant tau aggregation in both ipsilateral and contralateral hippocampi, but SI1-tau only induced tau pathology in the ipsilateral hippocampus, and SI2-tau and HS-tau failed to induce any detectable tau aggregation. These findings suggest that O-tau and SI1-tau have prion-like activities and may serve as seeds to recruit tau and template tau to aggregate, resulting in the propagation of tau pathology. Heterogeneity of tau pathology within AD brain results in different fractions with different biological and prion-like properties, which may pose a major challenge in targeting tau for development of effective therapeutic treatments.

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The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

BioMed Research International ◽

10.1155/2020/9895121 ◽

2020 ◽

Vol 2020 ◽

pp. 1-18 ◽

Cited By ~ 1

Author(s):

Brhane Teklebrhan Assefa ◽

Gebrehiwot Gebremedhin Tafere ◽

Dawit Zewdu Wondafrash ◽

Meles Tekie Gidey

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Plaque ◽

Current Evidence ◽

Negative Effects ◽

Disease Modifying Therapy ◽

Tau Aggregation ◽

And Oxidative Stress ◽

Remarkable Progress

Alzheimer’s disease is a multifactorial neurodegenerative disease characterized by progressive cognitive dysfunction. It is the most common form of dementia. The pathologic hallmarks of the disease include extracellular amyloid plaque, intracellular neurofibrillary tangles, and oxidative stress, to mention some of them. Despite remarkable progress in the understanding of the pathogenesis of the disease, drugs for cure or disease-modifying therapy remain somewhere in the distance. From recent time, the signaling molecule AMPK is gaining enormous attention in the AD drug research. AMPK is a master regulator of cellular energy metabolism, and recent pieces of evidence show that perturbation of its function is highly ascribed in the pathology of AD. Several drugs are known to activate AMPK, but their effect in AD remains to be controversial. In this review, the current shreds of evidence on the effect of AMPK activators in Aβ accumulation, tau aggregation, and oxidative stress are addressed. Positive and negative effects are reported with regard to Aβ and tauopathy but only positive in oxidative stress. We also tried to dissect the molecular interplays where the bewildering effects arise from.

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Intrinsic connectivity of the human brain provides scaffold for tau aggregation in clinical variants of Alzheimer's disease

Alzheimer s & Dementia ◽

10.1002/alz.044897 ◽

2020 ◽

Vol 16 (S1) ◽

Author(s):

Joseph Therriault ◽

Tharick A. Pascoal ◽

Melissa Savard ◽

Sulantha Mathotaarachchi ◽

Andréa Lessa Benedet ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Human Brain ◽

Intrinsic Connectivity ◽

Clinical Variants ◽

Tau Aggregation

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Aβ deposition is associated with increases in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.aaz2387 ◽

2020 ◽

Vol 6 (16) ◽

pp. eaaz2387 ◽

Cited By ~ 18

Author(s):

Niklas Mattsson-Carlgren ◽

Emelie Andersson ◽

Shorena Janelidze ◽

Rik Ossenkoppele ◽

Philip Insel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Pet ◽

Phosphorylated Tau ◽

Positron Emission ◽

Aβ Aggregation ◽

Tau Pet ◽

5Xfad Mice ◽

Tau Aggregation ◽

T Tau

The links between β-amyloid (Aβ) and tau in Alzheimer’s disease are unclear. Cognitively unimpaired persons with signs of Aβ pathology had increased cerebrospinal fluid (CSF) phosphorylated tau (P-tau181 and P-tau217) and total-tau (T-tau), which increased over time, despite no detection of insoluble tau aggregates [normal Tau positron emission tomography (PET)]. CSF P-tau and T-tau started to increase before the threshold for Amyloid PET positivity, while Tau PET started to increase after Amyloid PET positivity. Effects of Amyloid PET on Tau PET were mediated by CSF P-tau, and high CSF P-tau predicted increased Tau PET rates. Individuals with MAPT mutations and signs of tau deposition (but without Aβ pathology) had normal CSF P-tau levels. In 5xFAD mice, CSF tau increased when Aβ aggregation started. These results show that Aβ pathology may induce changes in soluble tau release and phosphorylation, which is followed by tau aggregation several years later in humans.

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