OSP-1 protects neurons from autophagic cell death induced by acute oxidative stress.

Oxidative stress, caused by the accumulation of reactive oxygen species (ROS), is a pathological factor in several incurable neurodegenerative conditions as well as in stroke. However, our knowledge of the genetic elements that can be manipulated to protect neurons from oxidative stress-induced cell death is still very limited. Here, using Caenorhabditis elegans as a model system, combined with the optogenetic tool KillerRed to spatially and temporally control ROS generation, we identify a previously uncharacterized gene, oxidative stress protective 1 (osp-1), that protects C.

Stimulation of the muscarinic receptor M4 regulates neural precursor cell proliferation and promotes adult hippocampal neurogenesis.

Cholinergic signaling plays a crucial role in the regulation of adult hippocampal neurogenesis; however, the mechanisms by which acetylcholine mediates neurogenic effects are not completely understood. Here, we report the expression of muscarinic acetylcholine receptor subtype M4 (M4 mAChR) on a subpopulation of neural precursor cells (NPCs) in the adult mouse hippocampus, and demonstrate that its pharmacological stimulation promotes their proliferation, thereby enhancing the production of new neurons in vivo. Using a targeted ablation approach, we also show that medial septum (MS) and the diagonal band of Broca (DBB) cholinergic neurons support both the survival and morphological maturation of adult-born neurons in the mouse hippocampus.

Longitudinal trajectories of basal forebrain volume in normal aging and Alzheimer's disease.

Dysfunction of the cholinergic basal forebrain (BF) system and amyloid-β (Aβ) deposition are early pathological features in Alzheimer's disease (AD). However, their association in early AD is not well-established. This study investigated the nature and magnitude of volume loss in the BF, over an extended period, in 516 older adults who completed Aβ-PET and serial magnetic resonance imaging scans.

Hericerin derivatives activates a pan-neurotrophic pathway in central hippocampal neurons converging to ERK1/2 signaling enhancing spatial memory.

The traditional medicinal mushroom Hericium erinaceus is known for enhancing peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. Here, we purified and identified biologically new active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons.

Cholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer's disease.

Although epidemiological studies indicate that sleep-disordered breathing (SDB) such as obstructive sleep apnea is a strong risk factor for the development of Alzheimer's disease (AD), the mechanisms of the risk remain unclear. Here we developed a method of modeling SDB in mice that replicates key features of the human condition: altered breathing during sleep, sleep disruption, moderate hypoxemia, and cognitive impairment. When we induced SDB in a familial AD model, the mice displayed exacerbation of cognitive impairment and the pathological features of AD, including increased levels of amyloid-beta and inflammatory markers, as well as selective degeneration of cholinergic basal forebrain neurons.

The basal forebrain volume reduction detected by MRI does not necessarily link with the cholinergic neuronal loss in the Alzheimer's disease mouse model.

Degeneration of cholinergic neurons in the basal forebrain (BF) contributes to cognitive impairment in Alzheimer's disease (AD) and other disorders. Atrophy of BF volume measured by structural MRI is thought to represent the loss of cholinergic neurons in this structure. As there are multiple types of neurons in the BF as well as glia and axons, whether this MRI measure actually reflects the change of cholinergic neurons has not been verified.

Reduced cortical cholinergic innervation measured using [F]-FEOBV PET imaging correlates with cognitive decline in mild cognitive impairment.

Dysfunction of the cholinergic basal forebrain (BF) neurotransmitter system, including cholinergic axon denervation of the cortex, plays an important role in cognitive decline and dementia. A validated method to directly quantify cortical cholinergic terminal integrity enables exploration of the involvement of this system in diverse cognitive profiles associated with dementia, particularly at a prodromal stage. In this study, we used the radiotracer [F]-fluoroethoxybenzovesamicol (FEOBV) as a direct measure of cholinergic terminal integrity and investigated its value for the assessment of cholinergic denervation in the cortex and associated cognitive deficits.

Frailty and severe mental illness: A systematic review and narrative synthesis.

Objective: Emerging evidence suggests that people with severe mental illness (SMI) have an increased risk of frailty. We conducted a systematic review to investigate the prevalence and correlates of frailty, as well as the efficacy of frailty interventions, in this population.

Methods: We searched databases from inception to 21 September 2021 for studies that assessed or intervened for frailty in relation to an SMI diagnosis.

High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair.

Neurotrophin signaling is essential for normal nervous system development and adult function. Neurotrophins are secreted proteins that signal via interacting with two neurotrophin receptor types: the multifaceted p75 neurotrophin receptor and the tropomyosin receptor kinase receptors. In vivo, neurons compete for the limited quantities of neurotrophins, a process that underpins neural plasticity, axonal targeting, and ultimately survival of the neuron.

Up-regulation of proBDNF/p75 signaling in antibody-secreting cells drives systemic lupus erythematosus.

Inappropriate expansion of antibody-secreting cells (ASCs) is typical of systemic lupus erythematosus (SLE), but the regulatory signaling of pathogenic ASCs is unclear. The present study shows that brain-derived neurotrophic factor precursor (proBDNF) and its high-affinity pan-75 neurotrophin receptor (p75) are highly expressed in CD19CD27CD38 ASCs in patients with SLE and in CD19CD44CD138 ASCs in lupus-like mice. The increased proBDNF ASCs were positively correlated with clinical symptoms and higher titers of autoantibodies in SLE.

Sleep and circadian rhythms in Parkinson's disease and preclinical models.

The use of animals as models of human physiology is, and has been for many years, an indispensable tool for understanding the mechanisms of human disease. In Parkinson's disease, various mouse models form the cornerstone of these investigations. Early models were developed to reflect the traditional histological features and motor symptoms of Parkinson's disease.

Is there a role for the p75 neurotrophin receptor in mediating degeneration during oxidative stress and after hypoxia?

Cholinergic basal forebrain (cBF) neurons are particularly vulnerable to degeneration following trauma and in neurodegenerative conditions. One reason for this is their characteristic expression of the p75 neurotrophin receptor (p75 ), which is up-regulated and mediates neuronal death in a range of neurological and neurodegenerative conditions, including dementia, stroke and ischaemia. The signalling pathway by which p75 signals cell death is incompletely characterised, but typically involves activation by neurotrophic ligands and signalling through c-Jun kinase, resulting in caspase activation via mitochondrial apoptotic signalling pathways.

Fast-Trk(B)ing the mechanism of antidepressants.

The mechanism by which antidepressants elicit clinical improvements has proven elusive. In a recent publication in Cell, Casarotto et al. (2021) reveal a surprising direct interaction between antidepressants and TrkB.

Cholinergic regulation of adult hippocampal neurogenesis and hippocampus-dependent functions.

The production and circuit integration of new neurons is one of the defining features of the adult mammalian hippocampus. A wealth of evidence has established that adult hippocampal neurogenesis is exquisitely sensitive to neuronal activity-mediated regulation. How these signals are interpreted and contribute to neurogenesis and hippocampal functions has been a subject of immense interest.

A validated quantitative method for the assessment of neuroprotective barrier impairment in neurodegenerative disease models.

The blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) are highly specialized structures that limit molecule entry from the blood and maintain homeostasis within the central nervous system (CNS). BBB and BSCB breakdown are associated with multiple neurodegenerative diseases. Given the key role of neuroprotective barrier impairment in neurodegeneration, it is important to identify an effective quantitative method to assess barrier integrity in animal models.

Partial deletion of p75 in large-diameter DRG neurons exerts no influence upon the survival of peripheral sensory neurons in vivo.

The p75 neurotrophin receptor (p75 ) is required for maintaining peripheral sensory neuron survival and function; however, the underlying cellular mechanism remains unclear. The general view is that expression of p75 by the neuron itself is required for maintaining sensory neuron survival and myelination in the peripheral nervous system (PNS). Adopting a neuronal-specific conditional knockout strategy, we demonstrate the partial depletion of p75 in neurons exerts little influence upon maintaining sensory neuron survival and peripheral nerve myelination in health and after demyelinating neuropathy.

Comparative studies of glial fibrillary acidic protein and brain-derived neurotrophic factor expression in two transgenic mouse models of Alzheimer's disease.

In Alzheimer's disease (AD) glial fibrillary acidic protein (GFAP) is expressed by reactive astrocytes surrounding β-amyloid (Aβ) plaques, whereas brain-derived neurotrophic factor (BDNF) levels are typically reduced. We compared the expression of GFAP, BDNF, and its precursor proBDNF in the dorsal hippocampus of two transgenic AD mouse models. APPSwe YAC mice expressing the APPSwe transgene on a yeast artificial chromosome (YAC) were assessed at age 4 and 21 months, and APPSwe/PS1dE9 mice co-expressing mutant amyloid precursor protein (APPSwe) and presenilin-1 (PS1dE9) were assessed at age 4 and 9 months.

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors.

Cholinergic basal forebrain (cBF) neurons are defined by their expression of the p75 neurotrophin receptor (p75) and tropomyosin-related kinase (Trk) neurotrophin receptors in addition to cholinergic markers. It is known that the neurotrophins, particularly nerve growth factor (NGF), mediate cholinergic neuronal development and maintenance. However, the role of neurotrophin signalling in regulating adult cBF function is less clear, although in dementia, trophic signalling is reduced and p75 mediates neurodegeneration of cBF neurons.

Blockade of TrkB but not p75 activates a subpopulation of quiescent neural precursor cells and enhances neurogenesis in the adult mouse hippocampus.

Brain-derived neurotrophic factor (BDNF) signaling plays a major role in the regulation of hippocampal neurogenesis in the adult brain. While the majority of studies suggest that this is due to its effect on the survival and differentiation of newborn neurons, it remains unclear whether this signaling directly regulates neural precursor cell (NPC) activity and which of its two receptors, TrkB or the p75 neurotrophin receptor (p75 ) mediates this effect. Here, we examined both the RNA and protein expression of these receptors and found that TrkB but not p75 receptors are expressed by hippocampal NPCs in the adult mouse brain.

The p75 neurotrophin receptor is required for the survival of neuronal progenitors and normal formation of the basal forebrain, striatum, thalamus and neocortex.

During development, the p75 neurotrophin receptor (p75) is widely expressed in the nervous system where it regulates neuronal differentiation, migration and axonal outgrowth. p75 also mediates the survival and death of newly born neurons, with functional outcomes being dependent on both timing and cellular context. Here, we show that knockout of p75 from embryonic day 10 (E10) in neural progenitors using a conditional Nestin-Cre p75 floxed mouse causes increased apoptosis of progenitor cells.

p110δ PI3-Kinase Inhibition Perturbs APP and TNFα Trafficking, Reduces Plaque Burden, Dampens Neuroinflammation, and Prevents Cognitive Decline in an Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD) is associated with the cleavage of the amyloid precursor protein (APP) to produce the toxic amyloid-β (Aβ) peptide. Accumulation of Aβ, together with the concomitant inflammatory response, ultimately leads to neuronal death and cognitive decline. Despite AD progression being underpinned by both neuronal and immunological components, therapeutic strategies based on dual targeting of these systems remains unexplored.

Peripheral Nerve Regeneration Is Independent From Schwann Cell p75 Expression.

Schwann cell reprogramming and differentiation are crucial prerequisites for neuronal regeneration and re-myelination to occur following injury to peripheral nerves. The neurotrophin receptor p75 has been identified as a positive modulator for Schwann cell myelination during development and implicated in promoting nerve regeneration after injury. However, most studies base this conclusion on results obtained from complete p75 knockout mouse models and cannot dissect the specific role of p75 expressed by Schwann cells.

Ultrafast fMRI of the rodent brain using simultaneous multi-slice EPI.

Increasing spatial and temporal resolutions of functional MRI (fMRI) measurement has been shown to benefit the study of neural dynamics and functional interaction. However, acceleration of rodent brain fMRI using parallel and simultaneous multi-slice imaging techniques is hampered by the lack of high-density phased-array coils for the small brain. To overcome this limitation, we adapted phase-offset multiplanar and blipped-controlled aliasing echo planar imaging (EPI) to enable simultaneous multi-slice fMRI of the mouse brain using a single loop coil on a 9.