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INTRODUCTION: Synaptic loss is an early prominent feature of Alzheimer's disease (AD). The recently developed novel synaptic vesicle 2A protein (SV2A) PET‐tracer UCB‐J has shown great promise in tracking synaptic loss in AD. However, there have been discrepancies between the findings and a lack of mechanistic insight. METHODS: Here we report the first extensive pre‐clinical validation studies for UCB‐J in control (CN; n = 11) and AD (n = 11) brains using a multidimensional approach of post‐mortem brain imaging techniques, radioligand binding, and biochemical studies. RESULTS AND DISCUSSION: We demonstrate that UCB‐J could target SV2A protein with high specificity and depict synaptic loss at synaptosome levels in AD brain regions compared to CNs. UCB‐J showed highest synaptic loss in AD hippocampus followed in descending order by frontal cortex, temporal cortex, parietal cortex, and cerebellum. 3H‐UCB‐J large brain‐section autoradiography and cellular/subcellular fractions binding studies indicated potential off‐target interaction with phosphorylated tau (p‐tau) species in AD brains, which could have subsequent clinical implications for imaging studies. Highlights: Synaptic positron emission tomography (PET)–tracer UCB‐J could target synaptic vesicle 2A protein (SV2A) with high specificity in Alzheimer's disease (AD) and control brains.Synaptic PET‐tracer UCB‐J could depict synaptic loss at synaptosome levels in AD brain regions compared to control.Potential off‐target interaction of UCB‐J with phosphorylated tau (p‐tau) species at cellular/subcellular levels could have subsequent clinical implications for imaging studies, warranting further investigations. [ABSTRACT FROM AUTHOR]

Reactive astrogliosis is an early event in the continuum of Alzheimer's disease (AD). Current advances in positron emission tomography (PET) imaging provide ways of assessing reactive astrogliosis in the living brain. In this review, we revisit clinical PET imaging and in vitro findings using the multi-tracer approach, and point out that reactive astrogliosis precedes the deposition of Aβ plaques, tau pathology, and neurodegeneration in AD. Furthermore, considering the current view of reactive astrogliosis heterogeneity—more than one subtype of astrocyte involved—in AD, we discuss how astrocytic body fluid biomarkers might fit into trajectories different from that of astrocytic PET imaging. Future research focusing on the development of innovative astrocytic PET radiotracers and fluid biomarkers may provide further insights into the heterogeneity of reactive astrogliosis and improve the detection of AD in its early stages. [ABSTRACT FROM AUTHOR]

Many dementias are propagated through the spread of "prion-like" misfolded proteins. This includes prion diseases themselves (such as Creutzfeldt-Jakob disease) and Alzheimer's disease (AD), for which no treatments are available to slow or stop progression. The M1 acetylcholine muscarinic receptor (M1 receptor) is abundant in the brain, and its activity promotes cognitive function in preclinical models and in patients with AD. Here, we investigated whether activation of the M1 receptor might slow the progression of neurodegeneration associated with prion-like misfolded protein in a mouse model of prion disease. Proteomic and transcriptomic analysis of the hippocampus revealed that this model had a molecular profile that was similar to that of human neurodegenerative diseases, including AD. Chronic enhancement of the activity of the M1 receptor with the positive allosteric modulator (PAM) VU0486846 reduced the abundance of prion-induced molecular markers of neuroinflammation and mitochondrial dysregulation in the hippocampus and normalized the abundance of those associated with neurotransmission, including synaptic and postsynaptic signaling components. PAM treatment of prion-infected mice prolonged survival and maintained cognitive function. Thus, allosteric activation of M1 receptors may reduce the severity of neurodegenerative diseases caused by the prion-like propagation of misfolded protein. Protecting against prions: Various neurodegenerative diseases are caused by misfolded proteins that aggregate and propagate through the brain and lack effective treatments. Because loss of acetylcholine signaling is associated with cognitive deficits in patients, Dwomoh et al. investigated the effect of enhancing acetylcholine signaling with positive allosteric modulators (PAMs) targeting the M1 acetylcholine receptor in a mouse model of prion disease. Systemic administration of PAMs reduced the abundance of prion-induced molecular markers in the hippocampus, restored various cognitive functions, and slowed disease progression in the mice. The proteomic and transcriptomic data from the prion mouse model substantially overlapped with those associated with Alzheimer's disease, suggesting that M1 receptor PAMs may be therapeutic in patients with prion and prion-like neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) is a 4R‐tauopathy causing problems with balance, movement, vision, speech, and swallowing. There is a lack of biomarkers for PSP, which often leads to misdiagnosis, prescription of incorrect pharmacological treatments and likely underdiagnosis. Synaptic vesicle protein 2A (SV2A) PET‐tracer UCB‐J has shown great promise in imaging synaptic loss in many neurodegenerative diseases in vivo including PSP. UCB‐J‐PET imaging holds great potential for the early and accurate diagnosis of PSP, however, there is a substantial gap in knowledge around the extent of synaptic loss in PSP. Hence, it is of utmost importance to investigate synaptic changes in PSP brains with UCB‐J and to establish its correlation with other synaptic and neuropathological markers to gain a deeper understanding of underlying mechanisms for future biomarker validation. Method: We performed specialized postmortem brain imaging (small and large frozen brain autoradiography) and radioligand binding assays (saturation, competition, and regional distribution), alongside immunohistochemistry and biochemical analyses in PSP and control (CN) brains. Result: Saturation studies in brain homogenates (BH) from the frontal cortex (FC) showed lower specific binding of 3H‐UCB‐J in PSP (Bmax: 348‐409 fmol/mg, Kd∼2.7nM) as compared to CN brains (Bmax:0.4‐0.5 pmol/mg, Kd∼3.5nM), indicating a loss in SV2A. Importantly, PSP brains showed much higher 3H‐UCB‐J specific binding in nuclear membrane P1‐fractions (Bmax 18.7‐22.1 pmol/mg, Kd ∼3.0nM) and synaptosomal‐membrane P2‐fractions (Bmax: 10.3‐12.3 pmol/mg, Kd∼2.4nM) as compared to BH (see above). Small section autoradiography showed lower 3H‐UCB‐J specific binding in PSP FC, but unexpectedly higher average specific binding in globus pallidus as compared to CN, suggesting regional differences and potential interaction with other brain tissue components/proteins. Conclusion: Our findings clearly demonstrate that there are region‐specific changes in UCB‐J binding in PSP brains compared to CN and further reflect the need for its in‐depth validation in postmortem brains and correlation with other synaptic and neuropathological markers. Moreover, P2 fraction is most optimal for reflecting synaptic loss with UCB‐J. The ongoing regional distribution, biochemical and immunostaining studies will help elucidate changes in synaptic integrity in PSP. [ABSTRACT FROM AUTHOR]

The oxidation of methionine residues in proteins occurs during oxidative stress and can lead to an alteration in protein function. The enzyme methionine sulfoxide reductase (Msr) reverses this modification. Here, we characterise the mammalian enzyme Msr B3. There are two splice variants of this enzyme that differ only in their N-terminal signal sequence, which directs the protein to either the endoplasmic reticulum (ER) or mitochondria. We demonstrate here that the enzyme can complement a bacterial strain, which is dependent on methionine sulfoxide reduction for growth, that the purified recombinant protein is enzymatically active showing stereospecificity towards R-methionine sulfoxide, and identify the active site and two resolving cysteine residues. The enzyme is efficiently recycled by thioredoxin only in the presence of both resolving cysteine residues. These results show that for this isoform of Msrs, the reduction cycle most likely proceeds through a three-step process. This involves an initial sulfenylation of the active site thiol followed by the formation of an intrachain disulfide with a resolving thiol group and completed by the reduction of this disulfide by a thioredoxin-like protein to regenerate the active site thiol. Interestingly, the enzyme can also act as an oxidase catalysing the stereospecific formation of R-methionine sulfoxide. This result has important implications for the role of this enzyme in the reversible modification of ER and mitochondrial proteins. [ABSTRACT FROM AUTHOR]

G protein‐coupled receptors (GPCRs) are a large family of cell surface receptors that play a critical role in nervous system function by transmitting signals between cells and their environment. They are involved in many, if not all, nervous system processes, and their dysfunction has been linked to various neurological disorders representing important drug targets. This overview emphasises the GPCRs of the nervous system, which are the research focus of the members of ERNEST COST action (CA18133) working group ‘Biological roles of signal transduction’. First, the (patho)physiological role of the nervous system GPCRs in the modulation of synapse function is discussed. We then debate the (patho)physiology and pharmacology of opioid, acetylcholine, chemokine, melatonin and adhesion GPCRs in the nervous system. Finally, we address the orphan GPCRs, their implication in the nervous system function and disease, and the challenges that need to be addressed to deorphanize them. [ABSTRACT FROM AUTHOR]