Postsynaptic p47phox regulates long-term depression in the hippocampus

Abstract It is well documented that reactive oxygen species (ROS) affects neurodegeneration in the brain. Several studies also implicate ROS in the regulation of synapse function and learning and memory processes, although the precise source of ROS generation within these contexts remains to be further explored. Here we show that postsynaptic superoxide generation through PKCζ-activated NADPH oxidase 2 (NOX2) is critical for long-term depression (LTD) of synaptic transmission in the CA1–Shaffer collateral synapse of the rat hippocampus. Specifically, PKCζ-dependent phosphorylation of p47phox at serine 316, a NOX2 regulatory subunit, is required for LTD but is not necessary for long-term potentiation (LTP). Our data suggest that postsynaptic p47phox phosphorylation at serine 316 is a key upstream determinant for LTD and synapse weakening

Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus

Evidence suggests that the stress hormones glucocorticoids (GCs) can cause cognitive deficits and neurodegeneration. Previous studies have found GCs facilitate physiological synapse weakening, termed long-term depression (LTD), though the precise mechanisms underlying this are poorly understood. Here we show that GCs activate glycogen synthase kinase-3 (GSK-3), a kinase crucial to synapse weakening signals. Critically, this ultimately leads to phosphorylation of the microtubule associated protein tau, specifically at the serine 396 residue, and this is a causal factor in the GC-mediated impairment of synaptic function. These findings reveal the link between GCs and synapse weakening signals, and the potential for stress-induced priming of neurodegeneration. This could have important implications for our understanding of how stress can lead to neurodegenerative disease

Baseline Sensitivity of Echinochloa crus-gall and E. oryzicola to Florpyrauxifen-Benzyl, a New Synthetic Auxin Herbicide, in Korea

Echinochloa species is one of the most problematic weed species due to its high competitiveness and increasing herbicide resistance. Florpyrauxifen-benzyl, a new auxin herbicide, was recently introduced for Echinochloa management; however, the potential risk for the development of herbicide resistance in Echinochloa species has not been well-investigated. Thus, this study was conducted to evaluate the baseline sensitivity of Echinochloa species to florpyrauxifen-benzyl to estimate the risk of future resistance development. A total of 70 and 71 accessions of Echinochloa crus-galli and Echinochloa oryzicola were collected from paddy fields in Korea, respectively. These two Echinochloa species were grown in plastic pots up to the 5-leaf stage, and treated with florpyrauxifen-benzyl at a range of doses from 2.2 g to 70.0 g a.i. ha–1. Nonlinear regression analyses revealed that GR50 values for E. oryzicola ranged from 4.54 g to 29.66 g a.i. ha–1, giving a baseline sensitivity index (BSI) of 6.53, while those for E. crus-galli ranged from 6.15 g to 16.06 g a.i. ha–1, giving a BSI of 2.61. Our findings suggest that E. oryzicola has a greater potential risk than E. crus-galli for the development of metabolism-based resistance to florpyrauxifen-benzyl

Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death

Funder: Alzheimer's Research UK (ARUK); doi: https://doi.org/10.13039/501100002283Abstract: The molecular events causing memory loss and neuronal cell death in Alzheimer’s disease (AD) over time are still unknown. Here we found that picomolar concentrations of soluble oligomers of synthetic beta amyloid (Aβ42) aggregates incubated with BV2 cells or rat astrocytes caused a sensitised response of Toll-like receptor 4 (TLR4) with time, leading to increased production of TNF-α. Aβ aggregates caused long term potentiation (LTP) deficit in hippocampal slices and predominantly neuronal cell death in co-cultures of astrocytes and neurons, which was blocked by TLR4 antagonists. Soluble Aβ aggregates cause LTP deficit and neuronal death via an autocrine/paracrine mechanism due to TLR4 signalling. These findings suggest that the TLR4-mediated inflammatory response may be a key pathophysiological process in AD

Beta amyloid aggregates induce sensitised TLR4 signalling causing long-term potentiation deficit and rat neuronal cell death

Funder: Alzheimer's Research UK (ARUK); doi: https://doi.org/10.13039/501100002283Abstract: The molecular events causing memory loss and neuronal cell death in Alzheimer’s disease (AD) over time are still unknown. Here we found that picomolar concentrations of soluble oligomers of synthetic beta amyloid (Aβ42) aggregates incubated with BV2 cells or rat astrocytes caused a sensitised response of Toll-like receptor 4 (TLR4) with time, leading to increased production of TNF-α. Aβ aggregates caused long term potentiation (LTP) deficit in hippocampal slices and predominantly neuronal cell death in co-cultures of astrocytes and neurons, which was blocked by TLR4 antagonists. Soluble Aβ aggregates cause LTP deficit and neuronal death via an autocrine/paracrine mechanism due to TLR4 signalling. These findings suggest that the TLR4-mediated inflammatory response may be a key pathophysiological process in AD

High-intensity walking in midlife is associated with improved memory in physically capable older adults

Background Little is known about the associations of midlife- and late life-initiated walking with Alzheimers disease (AD)-related cognitive decline in humans. We aimed to investigate whether high-intensity, prolonged, midlife-initiated walking is associated with changes in AD-related cognitive decline in physically capable older adults. Methods We studied 188 physically capable participants aged 65–90 years without dementia who underwent comprehensive clinical assessment, including of their walking modality (i.e., intensity, duration, midlife- or late life-onset), memory- or non-memory and total cognitive performance, and blood or nutritional biomarkers. Results The walking group showed better episodic memory (B = 2.852, SE = 1.214, β = 0.144, p = 0.020), but not non-memory cognition, than the non-walking group. High-intensity walking starting in midlife was significantly associated with better episodic memory (B = 9.360, SE = 3.314, β = 0.446, p = 0.005) compared to the non-walking group. In contrast, there were no differences in cognition according to walking duration, regardless of the onset time. The walking group also showed a similar association with overall cognition. Conclusions Among physically capable older adults without dementia, walking, particularly at high intensity and starting in midlife, is associated with improved episodic memory, an AD-related cognitive domain. Further attention should be paid to the role of walking in terms of AD prevention.This study was supported by grants from the Hallym University Research Fund (grant no. HURF-2020–56 and HURF-2022–13) and the Ministry of Science and ICT, Republic of Korea (grant no. NRF-2020R1G1A1099652). This study was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant no. RS-2023-00210820). The funding sources had no role in the study design, data collection, data analysis, data interpretation, writing of the manuscript, or decision to submit it for publication

Association between physical activity and episodic memory and the moderating effects of the apolipoprotein E ε4 allele and age

BackgroundAn abundance of evidence indicates that physical activity may protect against Alzheimer’s disease (AD) and related cognitive decline. However, little is known about the association between physical activity and AD-related cognitive decline according to age and the apolipoprotein E (APOE) ε4 allele (APOE4) as major risk factors. Therefore, we examined whether age and APOE4 status modulate the effects of physical activity on episodic memory as AD-related cognition in non-demented older adults.MethodsWe enrolled 196 adults aged between 65 and 90 years, with no dementia. All participants underwent comprehensive clinical assessments including physical activity evaluation and APOE genotyping. The AD-related cognitive domain was assessed by the episodic memory, as the earliest cognitive change in AD, and non-memory cognition for comparative purposes. Overall cognition was assessed by the total score (TS) of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery.ResultsWe found significant physical activity × age and physical activity × APOE4 interaction effects on episodic memory. Subgroup analyses indicated that an association between physical activity and increased episodic memory was apparent only in subjects aged > 70 years, and in APOE4-positive subjects.ConclusionOur findings suggest that physical activity has beneficial effects on episodic memory, as an AD-related cognitive domain, in individuals aged > 70 years and in APOE4-positive individuals. Physicians should take age and APOE4 status account into when recommending physical activity to prevent AD-related cognitive decline