Tau toxicity has been implicated in the emergence of synaptic dysfunction in Alzheimer’s disease (AD), but the mechanism by which tau alters synapse physiology and leads to cognitive decline is ...unclear. Here we report abnormal acetylation of K274 and K281 on tau, identified in AD brains, promotes memory loss and disrupts synaptic plasticity by reducing postsynaptic KIdney/BRAin (KIBRA) protein, a memory-associated protein. Transgenic mice expressing human tau with lysine-to-glutamine mutations to mimic K274 and K281 acetylation (tauKQ) exhibit AD-related memory deficits and impaired hippocampal long-term potentiation (LTP). TauKQ reduces synaptic KIBRA levels and disrupts activity-induced postsynaptic actin remodeling and AMPA receptor insertion. The LTP deficit was rescued by promoting actin polymerization or by KIBRA expression. In AD patients with dementia, we found enhanced tau acetylation is linked to loss of KIBRA. These findings suggest a novel mechanism by which pathogenic tau causes synaptic dysfunction and cognitive decline in AD pathogenesis.
•Dementia in AD is marked by enhanced acetylation of K281 and K274 on tau•Acetylated tau impairs memory encoding and AMPA receptor trafficking during LTP•Postsynaptic activity-dependent actin polymerization is blocked by acetylated tau•Loss of postsynaptic protein KIBRA underlies the tau-mediated LTP deficit
Tracy et al. identify K274 and K281 acetylation on tau as a contributing factor to synaptic dysfunction and memory loss related to Alzheimer’s disease. They show that acetylated tau disrupts postsynaptic signaling required for long-term synaptic strengthening.
Abstract
The Weyl semimetal (WSM), which hosts pairs of Weyl points and accompanying Berry curvature in momentum space near Fermi level, is expected to exhibit novel electromagnetic phenomena. ...Although the large optical/electronic responses such as nonlinear optical effects and intrinsic anomalous Hall effect (AHE) have recently been demonstrated indeed, the conclusive evidence for their topological origins has remained elusive. Here, we report the gigantic magneto-optical (MO) response arising from the topological electronic structure with intense Berry curvature in magnetic WSM Co
3
Sn
2
S
2
. The low-energy MO spectroscopy and the first-principles calculation reveal that the interband transitions on the nodal rings connected to the Weyl points show the resonance of the optical Hall conductivity and give rise to the giant intrinsic AHE in dc limit. The terahertz Faraday and infrared Kerr rotations are found to be remarkably enhanced by these resonances with topological electronic structures, demonstrating the novel low-energy optical response inherent to the magnetic WSM.
Several epidemiological and preclinical studies suggest that non‐steroidal anti‐inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can ...lower β‐amyloid (Aβ) production and inhibit neuroinflammation. However, follow‐up clinical trials, mostly using selective cyclooxygenase (COX)‐2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX‐1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro‐inflammatory stimuli including Aβ, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX‐1 inhibition, rather than COX‐2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20‐month‐old triple transgenic AD (3 × Tg‐AD) mice with the COX‐1 selective inhibitor SC‐560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC‐560 also reduced glial activation and brain expression of inflammatory markers in 3 × Tg‐AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX‐1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 × Tg‐AD mice. Thus, selective COX‐1 inhibition should be further investigated as a potential therapeutic approach for AD.
The role of COX‐1 in AD has not been considered carefully in part due to the presumed predominant role of COX‐2 in neuroinflammation. Here we show that the COX‐1 inhibitor SC‐560 reduces amyloid deposits and improves memory deficits in 3 × Tg‐AD mice. These results suggest that COX‐1 should be further considered as a potential target for therapeutic intervention.
Tauopathies, including frontotemporal dementia (FTD) and Alzheimer's disease (AD), are neurodegenerative diseases in which tau fibrils accumulate. Recent evidence supports soluble tau species as the ...major toxic species. How soluble tau accumulates and causes neurodegeneration remains unclear. Here we identify tau acetylation at Lys174 (K174) as an early change in AD brains and a critical determinant in tau homeostasis and toxicity in mice. The acetyl-mimicking mutant K174Q slows tau turnover and induces cognitive deficits in vivo. Acetyltransferase p300-induced tau acetylation is inhibited by salsalate and salicylate, which enhance tau turnover and reduce tau levels. In the PS19 transgenic mouse model of FTD, administration of salsalate after disease onset inhibited p300 activity, lowered levels of total tau and tau acetylated at K174, rescued tau-induced memory deficits and prevented hippocampal atrophy. The tau-lowering and protective effects of salsalate were diminished in neurons expressing K174Q tau. Targeting tau acetylation could be a new therapeutic strategy against human tauopathies.
In ferromagnets, an electric current generally induces a transverse Hall voltage in proportion to the internal magnetization. This effect is frequently used for the electrical readout of the spin-↑ ...and spin-↓ states. Although these properties are usually not expected in antiferromagnets, recent theoretical studies predicted that a non-coplanar antiferromagnetic order with finite scalar spin chirality—meaning a solid angle spanned by neighbouring spins—can induce a large spontaneous Hall effect even without a net magnetization or external magnetic field. This phenomenon—the spontaneous topological Hall effect—can potentially be used for the efficient electrical readout of antiferromagnetic states, but it has not been experimentally verified due to a lack of appropriate materials hosting such magnetism. Here we report the discovery of an all-in–all-out-type non-coplanar antiferromagnetic order in triangular lattice compounds CoTa3S6 and CoNb3S6. These compounds are reported to host unconventionally large spontaneous Hall effects despite their vanishingly small net magnetization, and our analysis reveals that it can be explained in terms of the topological Hall effect that originates from the fictitious magnetic field associated with scalar spin chirality. These results indicate that the scalar spin chirality mechanism offers a promising route to the realization of a giant spontaneous Hall response even in compensated antiferromagnets, and highlight intercalated van der Waals magnets as a promising quasi-two-dimensional material platform to enable various non-trivial ways of electrical reading and the possible writing of non-coplanar antiferromagnetic domains.The spontaneous topological Hall effect, combining non-coplanar antiferromagnetic order with finite scalar spin chirality in the absence of a magnetic field, is now experimentally demonstrated for the triangular lattice compounds CoTa3S6 and CoNb3S6.
Magnetic Weyl semimetals attract considerable interest not only for their topological quantum phenomena but also as an emerging materials class for realizing quantum anomalous Hall effect in the ...two-dimensional limit. A shandite compound Co3Sn2S2 with layered kagome-lattices is one such material, where vigorous efforts have been devoted to synthesize the two-dimensional crystal. Here, we report a synthesis of Co3Sn2S2 thin flakes with a thickness of 250 nm by chemical vapor transport method. We find that this facile bottom-up approach allows the formation of large-sized Co3Sn2S2 thin flakes of high-quality, where we identify the largest electron mobility (∼2600 cm2 V–1 s–1) among magnetic topological semimetals, as well as the large anomalous Hall conductivity (∼1400 Ω–1 cm–1) and anomalous Hall angle (∼32%) arising from the Berry curvature. Our study provides a viable platform for studying high-quality thin flakes of magnetic Weyl semimetal and stimulate further research on unexplored topological phenomena in the two-dimensional limit.
Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN ...polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.
Abstract Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta ...(Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3, 6, 9, 12, 16, 20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research.
Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation ...carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα.We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.
PDF
