APP Homodimers Transduce an Amyloid-β-Mediated Increase in Release Probability at Excitatory Synapses

SummaryAccumulation of amyloid-β peptides (Aβ), the proteolytic products of the amyloid precursor protein (APP), induces a variety of synaptic dysfunctions ranging from hyperactivity to depression that are thought to cause cognitive decline in Alzheimer’s disease. While depression of synaptic transmission has been extensively studied, the mechanisms underlying synaptic hyperactivity remain unknown. Here, we show that Aβ40 monomers and dimers augment release probability through local fine-tuning of APP-APP interactions at excitatory hippocampal boutons. Aβ40 binds to the APP, increases the APP homodimer fraction at the plasma membrane, and promotes APP-APP interactions. The APP activation induces structural rearrangements in the APP/Gi/o-protein complex, boosting presynaptic calcium flux and vesicle release. The APP growth-factor-like domain (GFLD) mediates APP-APP conformational changes and presynaptic enhancement. Thus, the APP homodimer constitutes a presynaptic receptor that transduces signal from Aβ40 to glutamate release. Excessive APP activation may initiate a positive feedback loop, contributing to hippocampal hyperactivity in Alzheimer’s disease

IGF-1 Receptor Differentially Regulates Spontaneous and Evoked Transmission via Mitochondria at Hippocampal Synapses.

The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer's disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca(2+) transients, while promoting spontaneous transmission and resting Ca(2+) level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca(2+) buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer's disease. VIDEO ABSTRACT.peerReviewe

A Stage 1 Pilot Cohort Exploring the Use of EMDR Therapy as a Videoconference Psychotherapy During COVID-19 With Frontline Mental Health Workers: A Proof of Concept Study Utilising a Virtual Blind 2 Therapist Protocol

Objective: The COVID-19 pandemic has had a major impact on the delivery of psychological treatment. Due to social distancing requirements, the provision moved to videoconferencing psychotherapy (VCP). There is a paucity of empirical data supporting the efficacy of EMDR therapy as a VCP. This stage 1 pilot study tested an EMDR therapy scripted protocol, such as Virtual Blind 2 Therapist (VB2Tr), on frontline mental health workers as a VCP regarding fitness for purpose, distinctiveness, relevance, and efficiency. Methods: A total of 24 participants were recruited for the study. The design included a one-session treatment intervention with pre, post, 1-month, and 6-month follow-up (FU) measurements. This treatment session used a “Blind 2 Therapist” EMDR therapy scripted protocol as videoconference psychotherapy that involves non-disclosure of traumatic memory. The research explored the treatment effect on the core characteristics of trauma memory, including subjective disturbance, belief systems, memory intensity (MI), vividness, and levels of emotionality. Additionally, the research explored participants’ experiences of adverse and benevolent childhood experiences (ACEs/BCEs) during their childhood. Results: Regarding the four tests, namely, fitness for purpose, distinctiveness, relevance, and efficiency, results are favourably suggesting potential clinical benefits of using EMDR as videoconference psychotherapy. Although this is a proof-of-concept study showing positive results, no clinical population or control group was used. The purpose of the study is to explore the potential for scalability toward a larger clinical trial. The treatment intervention was achieved irrespective of either ACEs/BCEs during childhood. Conclusion: The research tentatively supports the case for EMDR therapy as a credible treatment when used as video conference psychotherapy and in using the Blind 2 Therapist protocol. However, more research is needed to scale toward a clinical trial. Clinical Trial Registration: https://www.isrctn.com/ISRCTN12099530, identifier ISRCTN12099530

A wearable sensor and machine learning estimate step length in older adults and patients with neurological disorders

Abstract Step length is an important diagnostic and prognostic measure of health and disease. Wearable devices can estimate step length continuously (e.g., in clinic or real-world settings), however, the accuracy of current estimation methods is not yet optimal. We developed machine-learning models to estimate step length based on data derived from a single lower-back inertial measurement unit worn by 472 young and older adults with different neurological conditions, including Parkinson’s disease and healthy controls. Studying more than 80,000 steps, the best model showed high accuracy for a single step (root mean square error, RMSE = 6.08 cm, ICC(2,1) = 0.89) and higher accuracy when averaged over ten consecutive steps (RMSE = 4.79 cm, ICC(2,1) = 0.93), successfully reaching the predefined goal of an RMSE below 5 cm (often considered the minimal-clinically-important-difference). Combining machine-learning with a single, wearable sensor generates accurate step length measures, even in patients with neurologic disease. Additional research may be needed to further reduce the errors in certain conditions