Smuggle tau through a secret(ory) pathway

2021 ◽  
Vol 478 (14) ◽  
pp. 2921-2925
Author(s):  
Hao Xu (徐昊)
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Recent Work ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Nerve Cells ◽  
Transmembrane Domains ◽  
Tau Pathology ◽  
Microtubule Binding

Secretion of misfolded tau, a microtubule-binding protein enriched in nerve cells, is linked to the progression of tau pathology. However, the molecular mechanisms underlying tau secretion are poorly understood. Recent work by Lee et al. [Biochemical J. (2021) 478: 1471–1484] demonstrated that the transmembrane domains of syntaxin6 and syntaxin8 could be exploited for tau release, setting a stage for testing a novel hypothesis that has profound implications in tauopathies (e.g. Alzheimer's disease, FTDP-17, and CBD/PSP) and other related neurodegenerative diseases. The present commentary highlights the importance and limitations of the study, and discusses opportunities and directions for future investigations.

scholarly journals Corticotropin releasing factor-binding protein (CRF-BP) as a potential new therapeutic target in Alzheimer’s disease and stress disorders

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Dorien Vandael ◽  
Natalia V. Gounko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Therapeutic Target ◽  
Life Stress ◽  
Binding Protein ◽  
Critical Role ◽  
Treatment Strategies ◽  
Corticotropin Releasing Factor ◽  
Stress Disorders

Abstract Alzheimer’s disease is the most common cause of dementia and one of the most complex human neurodegenerative diseases. Numerous studies have demonstrated a critical role of the environment in the pathogenesis and pathophysiology of the disease, where daily life stress plays an important role. A lot of epigenetic studies have led to the conclusion that chronic stress and stress-related disorders play an important part in the onset of neurodegenerative disorders, and an enormous amount of research yielded valuable discoveries but has so far not led to the development of effective treatment strategies for Alzheimer’s disease. Corticotropin-releasing factor (CRF) is one of the major hormones and at the same time a neuropeptide acting in stress response. Deregulation of protein levels of CRF is involved in the pathogenesis of Alzheimer’s disease, but little is known about the precise roles of CRF and its binding protein, CRF-BP, in neurodegenerative diseases. In this review, we summarize the key evidence for and against the involvement of stress-associated modulation of the CRF system in the pathogenesis of Alzheimer’s disease and discuss how recent findings could lead to new potential treatment possibilities in Alzheimer’s disease by using CRF-BP as a therapeutic target.

scholarly journals PRECISION MEDICINE - THE GOLDEN GATE FOR DETECTION, TREATMENT AND PREVENTION OF ALZHEIMER’S DISEASE

2016 ◽  
pp. 1-17
Author(s):  
H. Hampel ◽  
S.E. O’Bryant ◽  
J.I. Castrillo ◽  
C. Ritchie ◽  
K. Rojkova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Precision Medicine ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Therapeutic Success ◽  
Preclinical Stage ◽  
Treatment And Prevention

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical “one-size-fits-all” approach in drug discovery towards biomarker guided “molecularly” tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

scholarly journals Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer’s disease pathologies

2019 ◽  
Vol 116 (18) ◽  
pp. 9094-9102 ◽  
Author(s):  
Jie Xiang ◽  
Zhi-Hao Wang ◽  
Eun Hee Ahn ◽  
Xia Liu ◽  
Shan-Ping Yu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Trophic Factor ◽  
Tau Pathology ◽  
Trkb Receptors ◽  
Repeat Domain

BDNF, an essential trophic factor implicated in synaptic plasticity and neuronal survival, is reduced in Alzheimer’s disease (AD). BDNF deficiency’s association with Tau pathology in AD is well documented. However, the molecular mechanisms accounting for these events remain incompletely understood. Here we show that BDNF deprivation triggers Tau proteolytic cleavage by activating δ-secretase [i.e., asparagine endopeptidase (AEP)], and the resultant Tau N368 fragment binds TrkB receptors and blocks its neurotrophic signals, inducing neuronal cell death. Knockout of BDNF or TrkB receptors provokes δ-secretase activation via reducing T322 phosphorylation by Akt and subsequent Tau N368 cleavage, inducing AD-like pathology and cognitive dysfunction, which can be restored by expression of uncleavable Tau N255A/N368A mutant. Blocking the Tau N368–TrkB complex using Tau repeat-domain 1 peptide reverses this pathology. Thus, our findings support that BDNF reduction mediates Tau pathology via activating δ-secretase in AD.

scholarly journals Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 150 ◽  
Author(s):  
Qian Cai ◽  
Yu Young Jeong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cellular Energy ◽  
Age Related ◽  
Mitochondrial Turnover ◽  
Neuronal Functions ◽  
Lateral Sclerosis

Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. Mitochondria are the main cellular energy powerhouses, supplying most of ATP by oxidative phosphorylation, which is required to fuel essential neuronal functions. Efficient removal of aged and dysfunctional mitochondria through mitophagy, a cargo-selective autophagy, is crucial for mitochondrial maintenance and neuronal health. Mechanistic studies into mitophagy have highlighted an integrated and elaborate cellular network that can regulate mitochondrial turnover. In this review, we provide an updated overview of the recent discoveries and advancements on the mitophagy pathways and discuss the molecular mechanisms underlying mitophagy defects in Alzheimer’s disease and other age-related neurodegenerative diseases, as well as the therapeutic potential of mitophagy-enhancing strategies to combat these disorders.

scholarly journals PDE4D And HCN1 Ultrastructure In Rhesus Macaque Entorhinal Cortex: Relevance For Aging And Alzheimer's Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 638-639
Author(s):  
Dibyadeep Datta ◽  
SueAnn Mentone ◽  
Amy Arnsten
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Rhesus Macaque ◽  
Entorhinal Cortex ◽  
Molecular Mechanisms ◽  
Calcium Release ◽  
Stellate Cell ◽  
Tau Pathology ◽  
Molecular Features

Abstract Tau pathology emerges in a distinct spatial and temporal pattern in Alzheimer’s Disease (AD). Anatomical studies in AD subjects and rhesus macaques show earliest signs of tau pathology in the stellate cell islands in entorhinal cortex (ERC) layer II. However, the molecular mechanisms that confer vulnerability to ERC layer II cells early in AD is unknown. cAMP-PKA magnification of calcium release has been seen in prefrontal cortex, associated with HCN channel opening to dynamically regulate synaptic strength. This process is regulated by phosphodiesterases (PDE), regulation that is lost with age. The current study examined whether this “signature of flexibility” could also be seen in layer II ERC, underlying vulnerability to tau pathology with aging. We used high-spatial resolution immunoEM to localize PDE4D and HCN1 in young rhesus macaque (7-10y) ERC layer II. Our results suggest that PDE4D was concentrated on the SER-spine apparatus and in postsynaptic density, and HCN1 expressed in the membrane near excitatory synapses in dendritic spines. Within dendritic shafts, PDE4D labeling was observed along microtubules and near mitochondria, whereas HCN1 was organized in discrete clusters along the plasma membrane. These data suggest that PDE4D is optimally positioned to modulate cAMP microdomains and control calcium extrusion from the SER. HCN1 channels are localized in subcompartments to facilitate dynamic physiological representation of sensory experience and visual space governed by cAMP-PKA signaling. The anatomical patterns in ERC layer II corroborate our findings in vulnerable glutamatergic circuits in prefrontal cortex, suggesting conserved molecular features in association cortices most susceptible in AD.

scholarly journals Possible Role of the Transglutaminases in the Pathogenesis of Alzheimer's Disease and Other Neurodegenerative Diseases

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Antonio Martin ◽  
Giulia De Vivo ◽  
Vittorio Gentile
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Polyglutamine Diseases ◽  
Post Translational Modification ◽  
Transglutaminase Activity

Transglutaminases are ubiquitous enzymes which catalyze posttranslational modifications of proteins. Recently, transglutaminase-catalyzed post-translational modification of proteins has been shown to be involved in the molecular mechanisms responsible for human diseases. Transglutaminase activity has been hypothesized to be involved also in the pathogenetic mechanisms responsible for several human neurodegenerative diseases. Alzheimer's disease and other neurodegenerative diseases, such as Parkinson's disease, supranuclear palsy, Huntington's disease, and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This paper focuses on the possible molecular mechanisms by which transglutaminase activity could be involved in the pathogenesis of Alzheimer's disease and other neurodegenerative diseases, and on the possible therapeutic effects of selective transglutaminase inhibitors for the cure of patients with diseases characterized by aberrant transglutaminase activity.

scholarly journals Microglia in Alzheimer’s Disease in the Context of Tau Pathology

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1439 ◽  
Author(s):  
Juan Ramón Perea ◽  
Marta Bolós ◽  
Jesús Avila
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Molecular Mechanisms ◽  
Senile Plaques ◽  
Protein A ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
The Impact

Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.

scholarly journals The proteome of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer’s disease

2021 ◽  
Vol 141 (3) ◽  
pp. 341-358
Author(s):  
David C. Hondius ◽  
Frank Koopmans ◽  
Conny Leistner ◽  
Débora Pita-Illobre ◽  
Regina M. Peferoen-Baert ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Folding ◽  
Neurofibrillary Tangles ◽  
Ribosomal Proteins ◽  
Molecular Mechanisms ◽  
Disease Process ◽  
Protein Markers ◽  
Granulovacuolar Degeneration ◽  
Tau Pathology

AbstractGranulovacuolar degeneration (GVD) is a common feature in Alzheimer’s disease (AD). The occurrence of GVD is closely associated with that of neurofibrillary tangles (NFTs) and GVD is even considered to be a pre-NFT stage in the disease process of AD. Currently, the composition of GVD bodies, the mechanisms associated with GVD and how GVD exactly relates to NFTs is not well understood. By combining immunohistochemistry (IHC) and laser microdissection (LMD) we isolated neurons with GVD and those bearing tangles separately from human post-mortem AD hippocampus (n = 12) using their typical markers casein kinase (CK)1δ and phosphorylated tau (AT8). Control neurons were isolated from cognitively healthy cases (n = 12). 3000 neurons per sample were used for proteome analysis by label free LC–MS/MS. In total 2596 proteins were quantified across samples and a significant change in abundance of 115 proteins in GVD and 197 in tangle bearing neurons was observed compared to control neurons. With IHC the presence of PPIA, TOMM34, HSP70, CHMP1A, TPPP and VXN was confirmed in GVD containing neurons. We found multiple proteins localizing specifically to the GVD bodies, with VXN and TOMM34 being the most prominent new protein markers for GVD bodies. In general, protein groups related to protein folding, proteasomal function, the endolysosomal pathway, microtubule and cytoskeletal related function, RNA processing and glycolysis were found to be changed in GVD neurons. In addition to these protein groups, tangle bearing neurons show a decrease in ribosomal proteins, as well as in various proteins related to protein folding. This study, for the first time, provides a comprehensive human based quantitative assessment of protein abundances in GVD and tangle bearing neurons. In line with previous functional data showing that tau pathology induces GVD, our data support the model that GVD is part of a pre-NFT stage representing a phase in which proteostasis and cellular homeostasis is disrupted. Elucidating the molecular mechanisms and cellular processes affected in GVD and its relation to the presence of tau pathology is highly relevant for the identification of new drug targets for therapy.

Sign in / Sign up

Export Citation Format

Share Document