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1. Network Diffusion Modeling Explains Longitudinal Tau PET Data

   https://doi.org/10.3389/fnins.2020.566876  

   Schäfer, Amelie; Mormino, Elizabeth C.; Kuhl, Ellen (December 2020, Frontiers in Neuroscience)

   null (Ed.)

   Alzheimer's disease is associated with the cerebral accumulation of neurofibrillary tangles of hyperphosphorylated tau protein. The progressive occurrence of tau aggregates in different brain regions is closely related to neurodegeneration and cognitive impairment. However, our current understanding of tau propagation relies almost exclusively on postmortem histopathology, and the precise propagation dynamics of misfolded tau in the living brain remain poorly understood. Here we combine longitudinal positron emission tomography and dynamic network modeling to test the hypothesis that misfolded tau propagates preferably along neuronal connections. We follow 46 subjects for three or four annual positron emission tomography scans and compare their pathological tau profiles against brain network models of intracellular and extracellular spreading. For each subject, we identify a personalized set of model parameters that characterizes the individual progression of pathological tau. Across all subjects, the mean protein production rate was 0.21 ± 0.15 and the intracellular diffusion coefficient was 0.34 ± 0.43. Our network diffusion model can serve as a tool to detect non-clinical symptoms at an earlier stage and make informed predictions about the timeline of neurodegeneration on an individual personalized basis. 

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2. Tau regulates Arc stability in neuronal dendrites via a proteasome-sensitive but ubiquitin-independent pathway

   https://doi.org/10.1016/j.jbc.2024.107237  

   Yakout, Dina W; Shroff, Ankit; Wei, Wei; Thaker, Vishrut; Allen, Zachary D; Sajish, Mathew; Nazarko, Taras Y; Mabb, Angela M (May 2024, Journal of Biological Chemistry)

   DeMartino, George (Ed.)

   Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule-associated protein tau, a main component of neurofibrillary tangles. Alzheimer’s disease (AD) is the most common type of tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Besides its role in stabilizing microtubules, tau is localized at postsynaptic sites and can regulate synaptic plasticity. The activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that plays a key role in synaptic plasticity, learning, and memory. Arc has been implicated in AD pathogenesis and regulates the release of amyloid-beta. We found that decreased Arc levels correlate with AD status and disease severity. Importantly, Arc protein was upregulated in the hippocampus of Tau KO mice and dendrites of Tau KO primary hippocampal neurons. Overexpression of tau decreased Arc stability in an activity-dependent manner, exclusively in neuronal dendrites, which was coupled to an increase in the expression of dendritic and somatic surface GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. The tau-dependent decrease in Arc was found to be proteasome-sensitive, yet independent of Arc ubiquitination and required the endophilin-binding domain of Arc. Importantly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. These observations provide a potential molecular basis for synaptic dysfunction mediated through the accumulation of tau in dendrites. Our findings confirm that Arc is misregulated in AD and further show a physiological role for tau in regulating Arc stability and AMPA receptor targeting. 

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3. Studies of aging nonhuman primates illuminate the etiology of early-stage Alzheimer's-like neuropathology: An evolutionary perspective

   https://doi.org/doi:10.1002/ajp.23254.  

   Arnsten, AFT; Datta, D; Preuss, TM (May 2021, American journal of primatology)

   null (Ed.)

   Tau pathology in Alzheimer's disease (AD) preferentially afflicts the limbic and recently enlarged association cortices, causing a progression of mnemonic and cognitive deficits. Although genetic mouse models have helped reveal mechanisms underlying the rare, autosomal-dominant forms of AD, the etiology of the more common, sporadic form of AD remains unknown, and is challenging to study in mice due to their limited association cortex and lifespan. It is also difficult to study in human brains, as early-stage tau phosphorylation can degrade postmortem. In contrast, rhesus monkeys have extensive association cortices, are long-lived, and can undergo perfusion fixation to capture early-stage tau phosphorylation in situ. Most importantly, rhesus monkeys naturally develop amyloid plaques, neurofibrillary tangles comprised of hyperphosphorylated tau, synaptic loss, and cognitive deficits with advancing age, and thus can be used to identify the early molecular events that initiate and propel neuropathology in the aging association cortices. Studies to date suggest that the particular molecular signaling events needed for higher cognition—for example, high levels of calcium to maintain persistent neuronal firing- lead to tau phosphorylation and inflammation when dysregulated with advancing age. The expression of NMDAR-NR2B (GluN2B)—the subunit that fluxes high levels of calcium—increases over the cortical hierarchy and with the expansion of association cortex in primate evolution, consistent with patterns of tau pathology. In the rhesus monkey dorsolateral prefrontal cortex, spines contain NMDAR-NR2B and the molecular machinery to magnify internal calcium release near the synapse, as well as phosphodiesterases, mGluR3, and calbindin to regulate calcium signaling. Loss of regulation with inflammation and/or aging appears to be a key factor in initiating tau pathology. The vast expansion in the numbers of these synapses over primate evolution is consistent with the degree of tau pathology seen across species: marmoset < rhesus monkey < chimpanzee < human, culminating in the vast neurodegeneration seen in humans with AD. 

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4. Dual amyloid cross-seeding reveals steric zipper-facilitated fibrillization and pathological links between protein misfolding diseases

   https://doi.org/10.1039/D0TB02958K  

   Zhang, Yanxian; Zhang, Mingzhen; Liu, Yonglan; Zhang, Dong; Tang, Yijing; Ren, Baiping; Zheng, Jie (April 2021, Journal of Materials Chemistry B)

   Amyloid cross-seeding, as a result of direct interaction and co-aggregation between different disease-causative peptides, is considered as a main mechanism for the spread of the overlapping pathology across different cells and tissues between different protein-misfolding diseases (PMDs). Despite the biomedical significance of amyloid cross-seeding in amyloidogenesis, it remains a great challenge to discover amyloid cross-seeding systems and reveal their cross-seeding structures and mechanisms. Herein, we are the first to report that GNNQQNY – a short fragment from yeast prion protein Sup35 – can cross-seed with both amyloid-β (Aβ, associated with Alzheimer's disease) and human islet amyloid polypeptide (hIAPP, associated with type II diabetes) to form β-structure-rich assemblies and to accelerate amyloid fibrillization. Dry, steric β-zippers, formed by the two β-sheets of different amyloid peptides, provide generally interactive and structural motifs to facilitate amyloid cross-seeding. The presence of different steric β-zippers in a variety of GNNQQNY-Aβ and GNNQQNY-hIAPP assemblies also explains amyloid polymorphism. In addition, alteration of steric zipper formation by single-point mutations of GNNQQNY and interactions of GNNQQNY with different Aβ and hIAPP seeds leads to different amyloid cross-seeding efficiencies, further confirming the existence of cross-seeding barriers. This work offers a better structural-based understanding of amyloid cross-seeding mechanisms linked to different PMDs. 

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5. Gallium nanoparticles as novel inhibitors of Aβ40 aggregation

   https://doi.org/10.1039/D1MA00461A  

   Torres, Kyabeth M.; Delgado, Ambar S.; Serrano, Erika R.; Falcón-Cruz, Nitza V.; Meléndez, Anamaris; Ramos, Idalia; Du, Deguo; Oyola, Rolando (August 2021, Materials Advances)

   Alzheimer's disease (AD) has been consistently related to the formation of senile amyloid plaques mainly composed of amyloid β (Aβ) peptides. The toxicity of Aβ aggregates has been indicated to be responsible for AD pathology. One scenario to decrease Aβ toxicity is the development of effective inhibitors against Aβ amyloid formation. In this study, we investigate the effect of gallium nitride nanoparticles (GaN NPs) as inhibitors of Aβ40 amyloid formation using a combination of biophysical approaches. Our results show that the lag phase of Aβ40 aggregation kinetics is significantly retarded by GaN NPs in a concentration dependent manner, implying the activity of GaN NPs in interfering with the formation of the crucial nucleus during Aβ aggregation. Our results also show that GaN NPs can reduce the amyloid fibril elongation rate in the course of the aggregation kinetics. It is speculated that the high polarization characteristics of GaN NPs may provoke a strong interaction between the particles and Aβ40 peptide and in this way decrease self-association of the peptide monomers to form amyloids. 

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