Suppression of mature TAU isoforms prevents Alzheimer's disease-like amyloid-beta oligomer-induced spine loss in rodent neurons.
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ABSTRACT:
SUBMITTER: Buchholz S
PROVIDER: S-EPMC10960270 | biostudies-literature | 2024 Aug
REPOSITORIES: biostudies-literature
Publications
Suppression of mature TAU isoforms prevents Alzheimer's disease-like amyloid-beta oligomer-induced spine loss in rodent neurons.
Buchholz Sarah S Zempel Hans H
Neural regeneration research 20231211 8
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Project description:AimThe amyloid precursor protein (APP) is endoproteolytically processed to generate either the neurotoxic beta-amyloid peptide (Aβ) or the secreted ectodomain APP alpha (sAPPα). While neurotrophic properties of sAPPα were suggested in several studies, it is still unclear if and how sAPPα counteracts pathogenic effects of Aβ. Direct comparisons with sAPPβ, produced in the Aβ-generating pathway, are missing in order to determine the role of sAPPα's carbonyl-terminal end in its possible neuroprotective activity.MethodsMouse neuronal primary cultures and hippocampal slices were treated with oligomeric Aβ42. The effects on tau phosphorylation and dendritic spine densities were assessed by western blot and confocal imaging, respectively. Co-administration of either sAPPα or sAPPβ was used to determine activity on Aβ-induced toxicity.Results/discussionWe found that oligomeric Aβ strongly increased AT8 and AT180 phosphorylation of tau and caused a loss of dendritic spines. SAPPα completely abolished Aβ effects whereas sAPPβ had no such rescue activity. Interestingly, sAPPα or sAPPβ alone neither affected tau phosphorylation nor dendritic spine numbers. Together, our data suggest that sAPPα specifically protects neurons against Aβ-dependent toxicity supporting the strategy of activating α-secretase-dependent endoproteolytic APP processing to increase sAPPα shedding from the neuronal plasma membrane as a therapeutic intervention for the protection of dendritic spines and phospho-tau-dependent toxicity in Alzheimer's disease.
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Project description:Multiple isoforms of aggregation-prone proteins are present under physiological conditions and have the propensity to assemble into co-oligomers with different properties from self-oligomers, but this process has not been quantitatively studied to date. We have investigated the amyloid-β (Aβ) peptide, associated with Alzheimer's disease, and the aggregation of its two major isoforms, Aβ40 and Aβ42, using a statistical mechanical modelling approach in combination with in vitro single-molecule fluorescence measurements. We find that at low concentrations of Aβ, corresponding to its physiological abundance, there is little free energy penalty in forming co-oligomers, suggesting that the formation of both self-oligomers and co-oligomers is possible under these conditions. Our model is used to predict the oligomer concentration and size at physiological concentrations of Aβ and suggests the mechanisms by which the ratio of Aβ42 to Aβ40 can affect cell toxicity. An increased ratio of Aβ42 to Aβ40 raises the fraction of oligomers containing Aβ42, which can increase the hydrophobicity of the oligomers and thus promote deleterious binding to the cell membrane and increase neuronal damage. Our results suggest that co-oligomers are a common form of aggregate when Aβ isoforms are present in solution and may potentially play a significant role in Alzheimer's disease.
| S-EPMC4921824 | biostudies-literature
Project description:The molecular pathogenesis of disorders arising from protein misfolding and aggregation is difficult to elucidate, involving a complex ensemble of intermediates, whose toxicity depends upon their state of progression along distinct processing pathways. To address the complex misfolding and aggregation that initiates the toxic cascade resulting in Alzheimer's disease (AD), we have developed a 2,2,6,6-tetramethylpiperidine-1-oxyl-4-amino-4-carboxylic acid spin-labeled amyloid-β (Aβ) peptide to observe its isoform-dependent interaction with the apoE protein. Although most individuals carry the E3 isoform of apoE, ∼15% of humans carry the E4 isoform, which is recognized as the most significant genetic determinant for Alzheimer's. ApoE is consistently associated with the amyloid plaque marker for AD. A vital question centers on the influence of the two predominant isoforms, E3 and E4, on Aβ peptide processing and hence Aβ toxicity. We used electron paramagnetic resonance (EPR) spectroscopy of incorporated spin labels to investigate the interaction of apoE with the toxic oligomeric species of Aβ in solution. EPR spectra of the spin-labeled side chain report on side chain and backbone dynamics as well as the spatial proximity of spins in an assembly. Our results indicate oligomer binding involves the C-terminal domain of apoE, with apoE3 reporting a much greater response through this conformational marker. Coupled with SPR binding measurements, apoE3 displays a higher affinity and capacity for the toxic Aβ oligomer. These findings support the hypothesis that apoE polymorphism and Alzheimer's risk can largely be attributed to the reduced ability of apoE4 to function as a clearance vehicle for the toxic form of Aβ.
| S-EPMC3016465 | biostudies-literature
Project description:Although tau is the primary constituent of neurofibrillary tangles (NFTs), evidence suggests that its toxic moiety is oligomeric in Alzheimer disease (AD). In this regard, tau oligomers correlate more strongly with neuronal loss than NFTs and exhibit neurotoxicity in preclinical AD models. Here, we investigated the spatiotemporal progression of oligomeric tau accumulation within the highly vulnerable cholinergic neurons of the nucleus basalis of Meynert (nbM) in AD. Tissue from subjects who died with a clinical diagnosis of no cognitive impairment, mild cognitive impairment, or AD was immunostained with the tau oligomeric complex 1 (TOC1) antibody, a marker of tau oligomers, and p75NTR, a cholinergic cell marker. Stereological estimates revealed a significant increase in the number of TOC1 nbM immunopositive (+) neurons with a concomitant decrease in p75NTR+ nbM neurons during the transition from mild cognitive impairment to AD. Immunofluorescence identified TOC1+ neurons that colocalized with the pretangle tau marker phospho-Ser422, which persisted into late stage NFTs immunoreactive for MN423. Analysis of the nbM subfields revealed a topographical caudal to rostral gradient of TOC1+ neurons during disease progression. Taken together, these data suggest that toxic tau oligomers accumulate caudorostrally in selectively vulnerable nbM neurons during the onset of AD.
| S-EPMC6251641 | biostudies-literature
Project description:Amyloid plays a critical role in the pathogenesis of Alzheimer's disease (AD) and can aggregate to form oligomers and fibrils in the brain. There is increasing evidence that highly toxic amyloid-β oligomers (AβOs) lead to tau protein aggregation, hyperphosphorylation, neuroinflammation, neuronal loss, synaptic loss, and dysfunction. Although the effects of AβOs on neurons have been investigated using conventional biochemical experiments, there are no established criteria for electrical evaluation. To this end, we explored electrophysiological changes in mouse hippocampal neurons (HT22) following exposure to AβOs and/or naringenin (Nar, a flavonoid compound) using electrical impedance spectroscopy (EIS). AβO-induced HT22 showed a decreased impedance amplitude and increased phase angle, and the addition of Nar reversed these changes. The characteristic frequency was markedly increased with AβO exposure, which was also reversed by Nar. The AβOs decreased intranuclear and cytoplasmic resistance and increased nucleus resistance and extracellular capacitance. Overall, the innovative construction of the eight-element CPE-equivalent circuit model further reflects that the pseudo-capacitance of the cell membrane and cell nucleus was increased in the AβO-induced group. This study conclusively revealed that AβOs induce cytotoxic effects by disrupting the resistance characteristics of unit membranes. The results further support that EIS is an effective technique for evaluating AβO-induced neuronal damage and microscopic electrical distinctions in the sub-microscopic structure of reactive cells.
| S-EPMC10892449 | biostudies-literature
Project description:Alzheimer's disease is a neurological disorder characterized by the overproduction and aggregation of amyloid-beta and the phosphorylation and intraneuronal accumulation of tau. These events promote synaptic dysfunction and loss, leading to neurodegeneration and cognitive deficits. Astrocytes are intimately associated with synapses and become activated under pathological conditions, becoming neurotoxic and detrimentally affecting synapses. Although it has been established that reducing neuronal tau expression prevents amyloid-beta-induced toxicity, the role of astrocytic tau in this setting remains understudied. Herein, we performed a series of astrocytic and neuronal primary cultures to evaluate the effects of decreasing astrocytic tau levels on astrocyte-mediated amyloid-beta-induced synaptic degeneration. Our results suggest that the downregulation of tau in astrocytes mitigates the loss of synapses triggered by their exposure to amyloid-beta. Additionally, the absence of tau from astrocytes promotes the upregulation of several synaptoprotective genes, followed by increased production of the neuroprotective factor Pentraxin 3. These results expand our understanding of the contribution of astrocytic tau to the neurodegenerative process induced by amyloid-beta-stimulation and how reducing astrocytic tau could improve astrocyte function by stimulating the expression of synaptoprotective factors. Reducing endogenous astrocytic tau expression could be a potential strategy to prevent synaptic damage in Alzheimer's disease and other neurological conditions.
| S-EPMC9527666 | biostudies-literature
Project description:BackgroundAccumulation of hyperphosphorylated tau is a major neuropathological feature of tauopathies including Alzheimer's disease (AD). Serum amyloid A (SAA), an acute-phase protein with cytokine-like property, has been implicated in amyloid deposition. It remains unclear whether SAA affects tau hyperphosphorylation.MethodsPotential involvement of SAA in tau hyperphosphorylation was examined using intracerebral injection of SAA, and in Saa3 (-/-) mice receiving systemic administration of lipopolysaccharide (LPS). Induced SAA expression and microglial activation were evaluated in these mice using real-time PCR and/or immunofluorescence staining. Cultured primary neuronal cells were treated with condition media (CM) from SAA-stimulated primary microglial cells. The alteration in tau hyperphosphorylation was determined using Western blotting.ResultsSaa3 is the predominant form of SAA proteins induced by LPS in the mouse brain that co-localizes with neurons. Overexpression of SAA by intracerebral injection attenuated tau hyperphosphorylation in the brain. Conversely, Saa3 deficiency enhanced tau phosphorylation induced by systemic LPS administration. Intracerebral injection of SAA also induced the activation of microglia in the brains. IL-10 released to CM from SAA-stimulated microglia attenuated tau hyperphosphorylation in cultured primary neurons. IL-10 neutralizing antibody reversed the effect of SAA in the attenuation of tau phosphorylation.ConclusionsLPS-induced expression of SAA proteins in the brain leads to the activation of microglia and release of IL-10, which in turn suppresses tau hyperphosphorylation in a mouse model of systemic inflammation.
| S-EPMC4736117 | biostudies-literature
Project description:Synapse degeneration and dendritic spine dysgenesis are believed to be crucial early steps in Alzheimer's disease (AD), and correlate with cognitive deficits in AD patients. Soluble amyloid beta (Aβ)-derived oligomers, also termed Aβ-derived diffusible ligands (ADDLs), accumulate in the brain of AD patients and play a crucial role in AD pathogenesis. ADDLs bind to mature hippocampal neurons, induce structural changes in dendritic spines and contribute to neuronal death. However, mechanisms underlying structural and toxic effects are not fully understood. Here, we report that ADDLs bind to cultured mature cortical pyramidal neurons and induce spine dysgenesis. ADDL treatment induced the rapid depletion of kalirin-7, a brain-specific guanine-nucleotide exchange factor for the small GTPase Rac1, from spines. Kalirin-7 is a key regulator of dendritic spine morphogenesis and maintenance in forebrain pyramidal neurons and here we show that overexpression of kalirin-7 prevents ADDL-induced spine degeneration. Taken together, our results suggest that kalirin-7 may play a role in the early events leading to synapse degeneration, and its pharmacological activation may prevent or delay synapse pathology in AD.
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Project description:Several studies have now supported the use of a tau lowering agent as a possible therapy in the treatment of tauopathy disorders, including Alzheimer's disease. In human Alzheimer's disease, however, concurrent amyloid-β deposition appears to synergize and accelerate tau pathological changes. Thus far, tau reduction strategies that have been tested in vivo have been examined in the setting of tau pathology without confounding amyloid-β deposition. To determine whether reducing total human tau expression in a transgenic model where there is concurrent amyloid-β plaque formation can still reduce tau pathology and protect against neuronal loss, we have taken advantage of the regulatable tau transgene in APP/PS1 × rTg4510 mice. These mice develop both neurofibrillary tangles as well as amyloid-β plaques throughout the cortex and hippocampus. By suppressing human tau expression for 6 months in the APP/PS1 × rTg4510 mice using doxycycline, AT8 tau pathology, bioactivity, and astrogliosis were reduced, though importantly to a lesser extent than lowering tau in the rTg4510 alone mice. Based on non-denaturing gels and proteinase K digestions, the remaining tau aggregates in the presence of amyloid-β exhibit a longer-lived aggregate conformation. Nonetheless, lowering the expression of the human tau transgene was sufficient to equally ameliorate thioflavin-S positive tangles and prevent neuronal loss equally well in both the APP/PS1 × rTg4510 mice and the rTg4510 cohort. Together, these results suggest that, although amyloid-β stabilizes tau aggregates, lowering total tau levels is still an effective strategy for the treatment of tau pathology and neuronal loss even in the presence of amyloid-β deposition.
| S-EPMC6022692 | biostudies-literature
Project description:Amyloid-beta (Aβ) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP(C)) selectively binds oligomeric Aβ and can mediate Alzheimer's disease-related phenotypes. We examined the specificity, distribution and signaling of Aβ-PrP(C) complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrP(C) is enriched in postsynaptic densities, and Aβ-PrP(C) interaction leads to Fyn kinase activation. Soluble Aβ assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrP(C) to activate Fyn. Aβ engagement of PrP(C)-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Aβ-induced dendritic spine loss and lactate dehydrogenase release required both PrP(C) and Fyn, and human familial Alzheimer's disease transgene-induced convulsive seizures did not occur in mice lacking PrP(C). These results delineate an Aβ oligomer signal transduction pathway that requires PrP(C) and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.
| S-EPMC3431439 | biostudies-literature