The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases
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ABSTRACT:
SUBMITTER: Wu M
PROVIDER: S-EPMC8579533 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:For more than five decades, the field of Alzheimer's disease (AD) has focused on two main hypotheses positing amyloid-beta (A?) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that confronts the leading Tau-based AD hypothesis and discuss the role of pTau modulating neural circuits and network connectivity. Additionally, we will briefly address the role of brain circuit alterations as a potential biomarker for detecting the prodromal AD stage.
| S-EPMC7481966 | biostudies-literature
Project description:In this review, we discuss the synaptic aspects of Tau pathology occurring during Alzheimer's disease (AD) and how this may relate to memory impairment, a major hallmark of AD. Whilst the clinical diagnosis of AD patients is a loss of working memory and long-term declarative memory, the histological diagnosis is the presence of neurofibrillary tangles of hyperphosphorylated Tau and Amyloid-beta plaques. Tau pathology spreads through synaptically connected neurons to impair synaptic function preceding the formation of neurofibrillary tangles, synaptic loss, axonal retraction and cell death. Alongside synaptic pathology, recent data suggest that Tau has physiological roles in the pre- or post- synaptic compartments. Thus, we have seen a shift in the research focus from Tau as a microtubule-stabilising protein in axons, to Tau as a synaptic protein with roles in accelerating spine formation, dendritic elongation, and in synaptic plasticity coordinating memory pathways. We collate here the myriad of emerging interactions and physiological roles of synaptic Tau, and discuss the current evidence that synaptic Tau contributes to pathology in AD.
| S-EPMC8428049 | biostudies-literature
Project description:BackgroundPerivascular spaces (PVS) have an important role in the elimination of metabolic waste from the brain. It has been hypothesized that the enlargement of PVS (ePVS) could be affected by pathophysiological mechanisms involved in Alzheimer's disease (AD), such as abnormal levels of CSF biomarkers. However, the relationship between ePVS and these pathophysiological mechanisms remains unknown.ObjectiveWe aimed to investigate the association between ePVS and CSF biomarkers of several pathophysiological mechanisms for AD. We hypothesized that ePVS will be associated to CSF biomarkers early in the AD continuum (i.e., amyloid positive cognitively unimpaired individuals). Besides, we explored associations between ePVS and demographic and cardiovascular risk factors.MethodsThe study included 322 middle-aged cognitively unimpaired participants from the ALFA + study, many within the Alzheimer's continuum. NeuroToolKit and Elecsys® immunoassays were used to measure CSF Aβ42, Aβ40, p-tau and t-tau, NfL, neurogranin, TREM2, YKL40, GFAP, IL6, S100, and α-synuclein. PVS in the basal ganglia (BG) and centrum semiovale (CS) were assessed based on a validated 4-point visual rating scale. Odds ratios were calculated for associations of cardiovascular and AD risk factors with ePVS using logistic and multinomial models adjusted for relevant confounders. Models were stratified by Aβ status (positivity defined as Aβ42/40 < 0.071).ResultsThe degree of PVS significantly increased with age in both, BG and CS regions independently of cardiovascular risk factors. Higher levels of p-tau, t-tau, and neurogranin were significantly associated with ePVS in the CS of Aβ positive individuals, after accounting for relevant confounders. No associations were detected in the BG neither in Aβ negative participants.ConclusionsOur results support that ePVS in the CS are specifically associated with tau pathophysiology, neurodegeneration, and synaptic dysfunction in asymptomatic stages of the Alzheimer's continuum.
| S-EPMC8340485 | biostudies-literature
Project description:Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate-i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau-, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.
| S-EPMC5928393 | biostudies-literature
Project description:Tau is implicated in more than 20 neurodegenerative diseases, including Alzheimer's disease. Under pathological conditions, Tau dissociates from axonal microtubules and missorts to pre- and postsynaptic terminals. Patients suffer from early synaptic dysfunction prior to Tau aggregate formation, but the underlying mechanism is unclear. Here we show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions, including synaptic vesicle mobility and release rate, lowering neurotransmission in fly and rat neurons. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. Moreover, an exogenously applied membrane-permeable peptide that competes for Tau-vesicle binding suppresses Tau-induced synaptic toxicity in rat neurons. Our work uncovers a presynaptic role of Tau that may be part of the early pathology in various Tauopathies and could be exploited therapeutically.
| S-EPMC5437271 | biostudies-literature
Project description:To test whether cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) concentration is elevated in Alzheimer's disease (AD) dementia and its associations with other hallmarks of AD, we examined the CSF GAP-43 measurements of 787 participants (245 cognitively normal (CN), 415 individuals with mild cognitive impairment (MCI) and 127 individuals with AD dementia) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Associations were investigated between CSF GAP-43 and clinical diagnosis, Aβ/tau/neurodegeneration (AT(N)) status, CSF and blood biomarkers of AD, cognitive measurements and brain neuroimaging findings. CSF GAP-43 levels were increased in patients with AD dementia (mean, 6331.05 pg/ml) compared with the CN (mean, 5001.05 pg/ml) and MCI (mean, 5118.8 pg/ml) (P < 0.001) groups. CSF GAP-43 correlated with CSF phosphorylated tau 181(p-tau) (r = 0.768, P < 0.001), and had high diagnostic accuracy in differentiating tau positive status vs. tau negative status (area under the receiver operating characteristic curve, 0.8606). CSF GAP-43 was particularly elevated among individuals with tau positive status. High CSF GAP-43 was associated with longitudinal deterioration of cognitive scores and brain neuroimaging findings. CSF GAP-43 was associated with a clinical diagnosis of AD dementia and with an individual's tau status, cognitive measurements and findings from neuroimaging. This study implies that CSF GAP-43 as a biomarker of synaptic dysfunction could predict the disease progression of AD patients.
| S-EPMC9576773 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder. A defining hallmark of the AD brain is the presence of intraneuronal neurofibrillary tangles (NFTs) which are made up of abnormally modified tau, with aberrant phosphorylation being the most studied posttranslational modification (PTM). Although the accumulation of tau as NFTs is an invariant feature of the AD brain, it has become evident that these insoluble aggregates are likely not the primary pathogenic form of tau, rather soluble forms of tau with abnormal PTMs are the mediators of toxicity. The most prevalent PTM on tau is phosphorylation, with the abnormal modification of specific residues on tau playing a key role in its toxicity. Even though it is widely accepted that tau with aberrant PTMs facilitates neurodegeneration, the precise cellular mechanisms remain unknown. Nonetheless, there is an evolving conceptual framework that an important contributing factor may be selective pathological tau species compromising mitochondrial biology. Understanding the mechanisms by which tau with site-specific PTM impacts mitochondria is crucial for understanding the role tau plays in AD. Here, we provide a brief introduction to tau and its phosphorylation and function in a physiological context, followed by a discussion of the impact of soluble phosphorylated tau species on neuronal processes in general and mitochondria more specifically. We also discuss how therapeutic strategies that attenuate pathological tau species in combination with treatments that improve mitochondrial biology could be a potential therapeutic avenue to mitigate disease progression in AD and other tauopathies.
| S-EPMC7544674 | biostudies-literature
Project description:Filamentous tau aggregates are hallmark lesions in numerous neurodegenerative diseases, including Alzheimer's disease (AD). Cell culture and animal studies showed that tau fibrils can undergo cell-to-cell transmission and seed aggregation of soluble tau, but this phenomenon was only robustly demonstrated in models overexpressing tau. In this study, we found that intracerebral inoculation of tau fibrils purified from AD brains (AD-tau), but not synthetic tau fibrils, resulted in the formation of abundant tau inclusions in anatomically connected brain regions in nontransgenic mice. Recombinant human tau seeded by AD-tau revealed unique conformational features that are distinct from synthetic tau fibrils, which could underlie the differential potency in seeding physiological levels of tau to aggregate. Therefore, our study establishes a mouse model of sporadic tauopathies and points to important differences between tau fibrils that are generated artificially and authentic ones that develop in AD brains.
| S-EPMC5110027 | biostudies-literature
Project description:Alzheimer's disease (AD) is a devastating neurodegenerative disorder that impacts a substantial number of individuals globally. Despite its widespread prevalence, there is currently no cure for AD. It is widely acknowledged that normal synaptic function holds a key role in memory, cognitive abilities, and the interneuronal transfer of information. As AD advances, symptoms including synaptic impairment, decreased synaptic density, and cognitive decline become increasingly noticeable. The importance of glial cells in the formation of synapses, the growth of neurons, brain maturation, and safeguarding the microenvironment of the central nervous system is well recognized. However, during AD progression, overactive glial cells can cause synaptic dysfunction, neuronal death, and abnormal neuroinflammation. Both neuroinflammation and synaptic dysfunction are present in the early stages of AD. Therefore, focusing on the changes in glia-synapse communication could provide insights into the mechanisms behind AD. In this review, we aim to provide a summary of the role of various glial cells, including microglia, astrocytes, oligodendrocytes, and oligodendrocyte precursor cells, in regulating synaptic dysfunction. This may offer a new perspective on investigating the underlying mechanisms of AD.
| S-EPMC10917533 | biostudies-literature
Project description:Synaptic dysfunction and neuronal excitatory/inhibitory imbalance have been implicated in Alzheimer's disease (AD) pathogenesis. Although intensive studies have been focused on the excitatory synaptic system, much less is known concerning the mechanisms mediating inhibitory synaptic dysfunction in AD. We reported previously that protocadherin-?C5 (Pcdh-?C5), a member of clustered Pcdh-? subfamily of cadherin-type synaptic adhesion proteins, functions to promote GABAergic synaptic transmission. We reveal here that Pcdh-?C5 is enriched in vesicular GABA transporter-positive synaptic puncta and its expression levels are increased in neuronal hyperexcitation conditions, upon ?-amyloid (A?) treatment, and in amyloid precursor protein (APP)/presenilin-1 (PS1)-transgenic mice of both sexes. This is associated with elevated levels of GABAergic proteins and enhanced synaptic inhibition. Genetic knock-down experiments showed that Pcdh-?C5 modulates spontaneous synaptic currents and A?-induced synaptic alterations directly. Our results support a model in which Pcdh-?C5 senses neuronal hyperexcitation to augment GABAergic inhibition. This adaptive mechanism may be dysregulated under chronic excitation conditions such as AD, leading to aberrant Pcdh-?C5 expression and associated synaptic dysfunction.SIGNIFICANCE STATEMENT Synaptic dysfunction is causal for Alzheimer's disease (AD). Here, we reveal a novel pathway that contributes GABAergic synaptic dysfunction in AD mediated by protocadherin-?C5. Our study not only identifies a new mechanism mediating excitatory/inhibitory balance in AD, but may also offer a new target for potential therapeutic intervention.
| S-EPMC5607468 | biostudies-literature