Physiological and Pathophysiological Implications of Synaptic Tau

Tauopathies encompass a broad range of neurodegenerative diseases featuring extensive neuronal death and cognitive decline. However, research over the past 30 years has failed to significantly advance our understanding of how tau causes dementia, limiting the design of rational therapeutics. It has become evident that we need to expand our understanding of tau in physiology, in order to delineate how tau may contribute to pathology. This review discusses recent evidence that has uncovered a novel aspect of tau function, based on its previously uncharacterized localization to the synapse. Here, multiple streams of evidence support a critical role for synaptic tau in the regulation of synapse physiology. In particular, long-term depression, a form of synaptic weakening, is dependent on the presence of tau in hippocampal neurons. The regulation of tau by specific phosphorylation events downstream of GSK-3β activation appears to be integral to this signaling role. We also describe how the regulation of synapse physiology by tau and its phosphorylation may inform our understanding of tauopathies and comorbid diseases. This work should provide a platform for future tau biology research in addition to therapeutic design.</jats:p

Focused Ultrasound Stimulation as a Neuromodulatory Tool for Parkinson’s Disease::A Scoping Review

Non-invasive focused ultrasound stimulation (FUS) is a non-ionising neuromodulatory technique that employs acoustic energy to acutely and reversibly modulate brain activity of deep-brain structures. It is currently being investigated as a potential novel treatment for Parkinson’s disease (PD). This scoping review was carried out to map available evidence pertaining to the provision of FUS as a PD neuromodulatory tool. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews, a search was applied to Ovid MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials on 13 January 2022, with no limits applied. In total, 11 studies were included: 8 were from China and 1 each from Belgium, South Korea and Taiwan. All 11 studies were preclinical (6 in vivo, 2 in vitro, 2 mix of in vivo and in vitro and 1 in silico). The preclinical evidence indicates that FUS is safe and has beneficial neuromodulatory effects on motor behaviour in PD. FUS appears to have a therapeutic role in influencing the disease processes of PD, and therefore holds great promise as an attractive and powerful neuromodulatory tool for PD. Though these initial studies are encouraging, further study to understand the underlying cellular and molecular mechanisms is required before FUS can be routinely used in PD

The role of melatonin in the onset and progression of type 3 diabetes

Abstract Alzheimer’s disease (AD) is defined by the excessive accumulation of toxic peptides, such as beta amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFT). The risk factors associated with AD include genetic mutations, aging, insulin resistance, and oxidative stress. To date, several studies that have demonstrated an association between AD and diabetes have revealed that the common risk factors include insulin resistance, sleep disturbances, blood brain barrier (BBB) disruption, and altered glucose homeostasis. Many researchers have discovered that there are mechanisms common to both diabetes and AD. AD that results from insulin resistance in the brain is termed “type 3 diabetes”. Melatonin synthesized by the pineal gland is known to contribute to circadian rhythms, insulin resistance, protection of the BBB, and cell survival mechanisms. Here, we review the relationship between melatonin and type 3 diabetes, and suggest that melatonin might regulate the risk factors for type 3 diabetes. We suggest that melatonin is crucial for attenuating the onset of type 3 diabetes by intervening in Aβ accumulation, insulin resistance, glucose metabolism, and BBB permeability

Transient ultrasound stimulation has lasting effects on neuronal excitability

Background Transcranial ultrasound stimulation can acutely modulate brain activity, but the lasting effects on neurons are unknown. Objective To assess the excitability profile of neurons in the hours following transient ultrasound stimulation. Methods Primary rat cortical neurons were stimulated with a 40 s, 200 kHz pulsed ultrasound stimulation or sham-stimulation. Intrinsic firing properties were investigated through whole-cell patch-clamp recording by evoking action potentials in response to somatic current injection. Recordings were taken at set timepoints following ultrasound stimulation: 0–2 h, 6–8 h, 12–14 h and 24–26 h. Transmission electron microscopy was used to assess synaptic ultrastructure at the same timepoints. Results In the 0–2 h window, neurons stimulated with ultrasound displayed an increase in the mean frequency of evoked action potentials of 32% above control cell levels (p = 0.023). After 4–6 h this increase was measured as 44% (p = 0.0043). By 12–14 h this effect was eliminated and remained absent 24–26 h post-stimulation. These changes to action potential firing occurred in conjunction with statistically significant differences between control and ultrasound-stimulated neurons in action potential half-width, depolarisation rate, and repolarisation rate, that were similarly eliminated by 24 h following stimulation. These effects occurred in the absence of alterations to intrinsic membrane properties or synaptic ultrastructure. Conclusion We report that stimulating neurons with 40 s of ultrasound enhances their excitability for up to 8 h in conjunction with modifications to action potential kinetics. This occurs in the absence of major ultrastructural change or modification of intrinsic membrane properties. These results can inform the application of transcranial ultrasound in experimental and therapeutic settings

Caspase-3 Activation via Mitochondria Is Required for Long-Term Depression and AMPA Receptor Internalization

NMDA receptor-dependent synaptic modifications, such as long-term potentiation (LTP) and long-term depression (LTD), are essential for brain development and function. LTD occurs mainly by the removal of AMPA receptors from the postsynaptic membrane, but the underlying molecular mechanisms remain unclear. Here, we show that activation of caspase-3 via mitochondria is required for LTD and AMPA receptor internalization in hippocampal neurons. LTD and AMPA receptor internalization are blocked by peptide inhibitors of caspase-3 and -9. In hippocampal slices from caspase-3 knockout mice, LTD is abolished whereas LTP remains normal. LTD is also prevented by overexpression of the anti-apoptotic proteins XIAP or Bcl-xL, and by a mutant Akt1 protein that is resistant to caspase-3 proteolysis. NMDA receptor stimulation that induces LTD transiently activates caspase-3 in dendrites, without causing cell death. These data indicate an unexpected causal link between the molecular mechanisms of apoptosis and LTD.National Institutes of Health (U.S.) (Fellowship F32-NS046126)National Institutes of Health (U.S.). Intramural Research ProgramNational Institute of Mental Health (U.S.

Adiponectin controls the apoptosis and the expression of tight junction proteins in brain endothelial cells through AdipoR1 under beta amyloid toxicity

AbstractAlzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by excessive beta amyloid (Aβ) deposition in brain, leading to blood–brain barrier (BBB) disruption. The mechanisms of BBB disruption in AD are still unclear, despite considerable research. The adipokine adiponectin is known to regulate various metabolic functions and reduce inflammation. Though adiponectin receptors have been reported in the brain, its role in the central nervous system has not been fully characterized. In the present study, we investigate whether adiponectin contributes to the tight junction integrity and cell death of brain endothelial cells under Aβ-induced toxicity conditions. We measured the expression of adiponectin receptors (AdipoR1 and AdipoR2) and the alteration of tight junction proteins in in vivo 5xFAD mouse brain. Moreover, we examined the production of reactive oxygen species (ROS) and the loss of tight junction proteins such as Claudin 5, ZO-1, and inflammatory signaling in in vitro brain endothelial cells (bEnd.3 cells) under Aβ toxicity. Our results showed that Acrp30 (a globular form of adiponectin) reduces the expression of proinflammatory cytokines and the expression of RAGE as Aβ transporters into brain. Moreover, we found that Acrp 30 attenuated the apoptosis and the tight junction disruption through AdipoR1-mediated NF-κB pathway in Aβ-exposed bEnd.3 cells. Thus, we suggest that adiponectin is an attractive therapeutic target for treating BBB breakdown in AD brain.</jats:p

A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs, GRIP and liprin-α

<p>Abstract</p> <p>Background</p> <p>Long-term depression (LTD) in the hippocampus can be induced by activation of different types of G-protein coupled receptors, in particular metabotropic glutamate receptors (mGluRs) and muscarinic acethycholine receptors (mAChRs). Since mGluRs and mAChRs activate the same G-proteins and isoforms of phospholipase C (PLC), it would be expected that these two forms of LTD utilise the same molecular mechanisms. However, we find a distinct mechanism of LTD involving GRIP and liprin-α.</p> <p>Results</p> <p>Whilst both forms of LTD require activation of tyrosine phosphatases and involve internalisation of AMPARs, they use different molecular interactions. Specifically, mAChR-LTD, but not mGluR-LTD, is blocked by peptides that inhibit the binding of GRIP to the AMPA receptor subunit GluA2 and the binding of GRIP to liprin-α. Thus, different receptors that utilise the same G-proteins can regulate AMPAR trafficking and synaptic efficacy via distinct molecular mechanisms.</p> <p>Conclusion</p> <p>Our results suggest that mAChR-LTD selectively involves interactions between GRIP and liprin-α. These data indicate a novel mechanism of synaptic plasticity in which activation of M1 receptors results in AMPAR endocytosis, via a mechanism involving interactions between GluA2, GRIP and liprin-α.</p

Cyclin Y inhibits plasticity-induced AMPA receptor exocytosis and LTP

Cyclin Y (CCNY) is a member of the cyclin protein family, known to regulate cell division in proliferating cells. Interestingly, CCNY is expressed in neurons that do not undergo cell division. Here, we report that CCNY negatively regulates long-term potentiation (LTP) of synaptic strength through inhibition of AMPA receptor trafficking. CCNY is enriched in postsynaptic fractions from rat forebrain and is localized adjacent to postsynaptic sites in dendritic spines in rat hippocampal neurons. Using live-cell imaging of a pH-sensitive AMPA receptor, we found that during LTP-inducing stimulation, CCNY inhibits AMPA receptor exocytosis in dendritic spines. Furthermore, CCNY abolishes LTP in hippocampal slices. Taken together, our findings demonstrate that CCNY inhibits plasticity-induced AMPA receptor delivery to synapses and thereby blocks LTP, identifying a novel function for CCNY in post-mitotic cells

The reemergence of long-term potentiation in aged Alzheimer's disease mouse model

Mouse models of Alzheimer’s disease (AD) have been developed to study the pathophysiology of amyloid β protein (Aβ) toxicity, which is thought to cause severe clinical symptoms such as memory impairment in AD patients. However, inconsistencies exist between studies using these animal models, specifically in terms of the effects on synaptic plasticity, a major cellular model of learning and memory. Whereas some studies find impairments in plasticity in these models, others do not. We show that long-term potentiation (LTP), in the CA1 region of hippocampal slices from this mouse, is impared at Tg2576 adult 6–7 months old. However, LTP is inducible again in slices taken from Tg2576 aged 14–19 months old. In the aged Tg2576, we found that the percentage of parvalbumin (PV)-expressing interneurons in hippocampal CA1-3 region is significantly decreased, and LTP inhibition or reversal mediated by NRG1/ErbB signaling, which requires ErbB4 receptors in PV interneurons, is impaired. Inhibition of ErbB receptor kinase in adult Tg2576 restores LTP but impairs depotentiation as shown in aged Tg2576. Our study suggests that hippocampal LTP reemerges in aged Tg2576. However, this reemerged LTP is an insuppressible form due to impaired NRG1/ErbB signaling, possibly through the loss of PV interneurons