scholarly journals Protein Tau: Prime Cause of Synaptic and Neuronal Degeneration in Alzheimer's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Natalia Crespo-Biel ◽  
Clara Theunis ◽  
Fred Van Leuven
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Clinical Symptoms ◽  
Neuronal Degeneration ◽  
Experimental Models ◽  
Preclinical Models ◽  
Protein Tau ◽  
Tau Isoforms ◽  
Late Event

The microtubule-associated protein Tau (MAPT) is a major component of the pathogenesis of a wide variety of brain-damaging disorders, known as tauopathies. These include Alzheimer's disease (AD), denoted as secondary tauopathy because of the obligatory combination with amyloid pathology. In all tauopathies, protein Tau becomes aberrantly phosphorylated, adopts abnormal conformations, and aggregates into fibrils that eventually accumulate as threads in neuropil and as tangles in soma. The argyrophilic neurofibrillary threads and tangles, together denoted as NFT, provide the postmortem pathological diagnosis for all tauopathies. In AD, neurofibrillary threads and tangles (NFTs) are codiagnostic with amyloid depositions but their separated and combined contributions to clinical symptoms remain elusive. Importantly, NFTs are now considered a late event and not directly responsible for early synaptic dysfunctions. Conversely, the biochemical and pathological timeline is not exactly known in human tauopathy, but experimental models point to smaller Tau-aggregates, termed oligomers or multimers, as synaptotoxic in early stages. The challenge is to molecularly define these Tau-isoforms that cause early cognitive and synaptic impairments. Here, we discuss relevant studies and data obtained in our mono- and bigenic validated preclinical models, with the perspective of Tau as a therapeutic target.

scholarly journals Supplementation with Curcuma longa Reverses Neurotoxic and Behavioral Damage in Models of Alzheimer’s Disease: A Systematic Review

2019 ◽  
Vol 17 (5) ◽  
pp. 406-421 ◽  
Author(s):  
Ianara Mendonça da Costa ◽  
Marco Aurelio de Moura Freire ◽  
José Rodolfo Lopes de Paiva Cavalcanti ◽  
Dayane Pessoa de Araújo ◽  
Bianca Norrara ◽  
...  
Keyword(s):  
Systematic Review ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Curcuma Longa ◽  
Senile Plaques ◽  
Experimental Models ◽  
Cochrane Library

Background: The formation of senile plaques and neurofibrillary tangles of the tau protein are the main pathological mechanism of Alzheimer’s disease (AD). Current therapies for AD offer discrete benefits to the clinical symptoms and do not prevent the continuing degeneration of neuronal cells. Therefore, novel therapeutic strategies have long been investigated, where curcumin (Curcuma longa) has shown some properties that can prevent the deleterious processes involved in neurodegenerative diseases. Objective: The aim of the present work is to review studies that addressed the effects of curcumin in experimental models (in vivo and in vitro) for AD. Method: This study is a systematic review conducted between January and June 2017, in which a consultation of scientific articles from indexed periodicals was carried out in Science Direct, United States National Library of Medicine (PubMed), Cochrane Library and Scielo databases, using the following descriptors: “Curcuma longa”, “Curcumin” and “Alzheimer’s disease”. Results: A total of 32 studies were analyzed, which indicated that curcumin supplementation reverses neurotoxic and behavioral damages in both in vivo and in vitro models of AD. Conclusion: The administration of curcumin in experimental models seems to be a promising approach in AD, even though it is suggested that additional studies must be conducted using distinct doses and through other routes of administration.

Perturbed endoplasmic reticulum function, synaptic apoptosis and the pathogenesis of Alzheimer's disease

2001 ◽  
Vol 67 ◽  
pp. 151-162 ◽  
Author(s):  
Mark P. Mattson ◽  
Devin S. Gary ◽  
Sic L. Chan ◽  
Wenzhen Duan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Neuronal Degeneration ◽  
Focal Point ◽  
Experimental Models ◽  
Proteolytic Processing ◽  
App Processing ◽  
The Impact ◽  
Er Calcium

Endoplasmic reticulum (ER) appears to be a focal point for alterations that result in neuronal dysfunction and death in Alzheimer's disease (AD). Aberrant proteolytic processing and/or trafficking of the ϐ-amyloid precursor protein (APP) in ER may promote neuronal degeneration by increasing the levels of the neurotoxic forms of ϐ-amyloid (Aϐ) and by decreasing the levels of the neuroprotective secreted form of APP (sAPPα). Some cases of AD are caused by mutations in the genes encoding presenilin 1 (PS1). When expressed in cultured neuronal cells and transgenic mice, PS1 mutations cause abnormalities in ER calcium homoeostasis, enhancing the calcium responses to stimuli that activate IP3- and ryanodine-sensitive ER calcium pools. Two major consequences of this disrupted ER calcium regulation are altered proteolytic processing of APP and increased vulnerability of neurons to apoptosis and excitotoxicity. The impact of PS1 mutations and aberrant APP processing is particularly great in synaptic terminals. Perturbed synaptic calcium homoeostasis promotes activation of apoptotic cascades involving production of Par-4 (prostate apoptosis response-4), mitochondrial dysfunction and caspase activation. Aϐ 42 (the 42-amino-acid form of Aϐ) induces membrane lipid peroxidation in synapses and dendrites resulting in impairment of membrane ion-motive ATPases and glucose and glutamate transporters. This disrupts synaptic ion and energy homoeostasis thereby promoting synaptic degeneration. In contrast, sAPPα activates signalling pathways that protect synapses against excitotoxicity and apoptosis. In the more common sporadic forms of AD, the initiating causes of the neurodegenerative cascade are less well defined, but probably involve increased levels of oxidative stress and impaired energy metabolism. Such alterations have been shown to disrupt neuronal calcium homoeostasis in experimental models, and may therefore feed into the same neurodegenerative cascade initiated by mutations in presenilins and APP. Perturbed synaptic ER calcium homoeostasis and consequent alterations in APP processing appear to be pivotal events in both sporadic and familial forms of AD.

Tau alternative splicing in familial and sporadic tauopathies

2012 ◽  
Vol 40 (4) ◽  
pp. 677-680 ◽  
Author(s):  
Michael Niblock ◽  
Jean-Marc Gallo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alternative Splicing ◽  
Chromosome 17 ◽  
Binding Motif ◽  
Neuronal Viability ◽  
Protein Tau ◽  
Rna Analysis ◽  
Tau Isoforms ◽  
Exon 10

Six tau isoforms differing in their affinity for microtubules are produced by alternative splicing from the MAPT (microtubule-associated protein tau) gene in adult human brain. Several MAPT mutations causing the familial tauopathy, FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17), affect alternative splicing of exon 10, encoding a microtubule-binding motif. Advanced RNA analysis methods have suggested that levels of exon 10-containing MAPT mRNA are elevated in Alzheimer's disease. Furthermore, the MAPT H1 haplotype, associated with Alzheimer's disease, promotes exon 10 inclusion in MAPT mRNA. Thus an accurate regulation of tau alternative splicing is critical for the maintenance of neuronal viability, and its alteration might be a contributing factor to Alzheimer's disease. Tau alternative splicing could represent a target for therapeutic intervention to delay the progression of pathology in familial as well as sporadic tauopathies.

Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms

Brain ◽  
2021 ◽  
Author(s):  
Masato Hosokawa ◽  
Masami Masuda-Suzukake ◽  
Hiroshi Shitara ◽  
Aki Shimozawa ◽  
Genjiro Suzuki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Corticobasal Degeneration ◽  
Pick's Disease ◽  
Intracerebral Injection ◽  
Pick’S Disease ◽  
Species Barrier ◽  
Alternative Mrna Splicing ◽  
Tau Isoforms

Abstract The phenomenon of "prion-like propagation" in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein of tau contains a microtubule-binding domain which consists of 3-repeats or 4-repeats due to alternative mRNA splicing of transcripts for the Microtubule-associated protein of tau gene. Although a number of models for tau propagation have been reported, most utilize 4-repeat human tau transgenic mice or adult wild-type mice expressing only endogenous 4-repeat tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3-repeat and 4-repeat tau accumulate simultaneously, or that of Pick’s disease in which only 3-repeat tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3-repeat and 4-repeat tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer’s disease (3- and 4-repeat tauopathy), corticobasal degeneration (4-repeat tauopathy) or Pick’s disease (3-repeat tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3- and 4-repeat tau in Alzheimer’s disease-injected brains, 4-repeat tau only in corticobasal degeneration-injected brains, and 3-repeat tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick’s body-like inclusions were observed in Pick’s disease-injected mice, and accumulations characteristic of Pick’s disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick’s disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3- and 4-repeat-isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

Polymorphisms in the microtubuli associated protein tau and Alzheimer’s disease

2004 ◽  
Vol 36 (05) ◽  
Author(s):  
L Weller ◽  
F Faltraco ◽  
E Heimberg ◽  
S Teipel ◽  
B Bondy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Tau

An Insight in Pathophysiological Mechanism of Alzheimer’s Disease and its Management using Plant Natural Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Zeba Firdaus ◽  
Tryambak Deo Singh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Natural Products ◽  
Side Effects ◽  
Neuronal Degeneration ◽  
Acetylcholinesterase Inhibitor ◽  
Pathophysiological Mechanism ◽  
Limited Effectiveness ◽  
Drug Development Research ◽  
Sites Of Action

: Alzheimer’s disease (AD) is an age-associated nervous system disorder and a leading cause of dementia worldwide. Clinically it is described by cognitive impairment, and pathophysiologically by deposition of amyloid plaques and neurofibrillary tangles in the brain and neurodegeneration. This article reviews the pathophysiology, course of neuronal degeneration, and the various possible hypothesis of AD progression. These hypotheses include amyloid cascade, tau hyperphosphorylation, cholinergic disruption, metal dysregulation, vascular dysfunction, oxidative stress, and neuroinflammation. There is an exponential increase in the occurrence of the AD in recent few years that indicate an urgent need to develop some effective treatment. Currently, only 2 classes of drugs are available for AD treatment namely acetylcholinesterase inhibitor and NMDA receptor antagonist. Since AD is a complex neurological disorder and these drugs use a single target approach, alternatives are needed due to limited effectiveness and unpleasant side-effects of these drugs. Currently, plants have been used for drug development research especially because of their multiple sites of action and fewer side effects. Uses of some herbs and phytoconstituents for the management of neuronal disorders like AD have been documented in this article. Phytochemical screening of these plants shows the presence of many beneficial constituents like flavonoids, triterpenes, alkaloids, sterols, polyphenols, and tannins. These compounds show a wide array of pharmacological activities such as anti-amyloidogenic, anticholinesterase, and antioxidant. This article summarizes the present understanding of AD progression and gathers biochemical evidence from various works on natural products that can be useful in the management of this disease.

Sign in / Sign up

Export Citation Format

Share Document