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INTRODUCTION: Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)‐hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive. METHODS: We investigated the effects of HNK on hippocampal protein synthesis, long‐term potentiation (LTP), and memory in AD mouse models. RESULTS: HNK activated extracellular signal‐regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid‐β oligomers (AβO)‐infused mice in an ERK1/2‐dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. DISCUSSION: Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD. Highlights: The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways.HNK corrects hippocampal synaptic and memory defects in two mouse models of AD.Rescue of synaptic and memory impairments by HNK depends on ERK signaling.HNK corrects aberrant transcriptional signatures in APP/PS1 mice. [ABSTRACT FROM AUTHOR]

The amyloid hypothesis posits that the amyloid-beta (A[beta]) protein precedes and requires microtubule-associated protein tau in a sort of trigger-bullet mechanism leading to Alzheimer's disease (AD) pathology. This sequence of events has become dogmatic in the AD field and is used to explain clinical trial failures due to a late start of the intervention when A[beta] already activated tau. Here, using a multidisciplinary approach combining molecular biological, biochemical, histopathological, electrophysiological, and behavioral methods, we demonstrated that tau suppression did not protect against A[beta]-induced damage of long-term synaptic plasticity and memory, or from amyloid deposition. Tau suppression could even unravel a defect in basal synaptic transmission in a mouse model of amyloid deposition. Similarly, tau suppression did not protect against exogenous oligomeric tau-induced impairment of long-term synaptic plasticity and memory. The protective effect of tau suppression was, in turn, confined to short-term plasticity and memory. Taken together, our data suggest that therapies downstream of A[beta] and tau together are more suitable to combat AD than therapies against one or the other alone., Introduction The amyloid cascade hypothesis dominates in the Alzheimer's disease (AD) field. It posits that amyloid-[beta] (A[beta]) and tau proteins are placed in a series with A[beta] upstream of tau, [...]

Background: Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer's disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved. Methods: Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices. Results: Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP. Conclusions: Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

After several years of research in the field of Alzheimer's disease (AD), it is still unclear how amyloid-beta (Aβ) and Tau, two key hallmarks of the disease, mediate the neuropathogenic events that lead to AD. Current data challenge the "Amyloid Cascade Hypothesis" that has prevailed in the field of AD, stating that Aβ precedes and triggers Tau pathology that will eventually become the toxic entity in the progression of the disease. This perspective also led the field of therapeutic approaches towards the development of strategies that target Aβ or Tau. In the present review, we discuss recent literature regarding the neurotoxic role of both Aβ and Tau in AD, as well as their physiological function in the healthy brain. Consequently, we present studies suggesting that Aβ and Tau act independently of each other in mediating neurotoxicity in AD, thereafter, re-evaluating the "Amyloid Cascade Hypothesis" that places Tau pathology downstream of Aβ. More recent studies have confirmed that both Aβ and Tau could propagate the disease and induce synaptic and memory impairments via the amyloid precursor protein (APP). This finding is not only interesting from a mechanistic point of view since it provides better insights into the AD pathogenesis but also from a therapeutic point of view since it renders APP a common downstream effector for both Aβ and Tau. Subsequently, therapeutic strategies that act on APP might provide a more viable and physiologically relevant approach for targeting AD. [ABSTRACT FROM AUTHOR]

Background: Clinicopathological studies of Alzheimer's disease (AD) have demonstrated that synaptic or neuronal loss and clinical cognitive decline do not reliably correlate with fibrillar amyloid burden. We created a transgenic mouse model overexpressing Dutch (E693Q) mutant human amyloid precursor protein (APP) driven by the pan‐neuronal Thy1 promoter. Accumulation of APP carboxyl‐terminal fragments was observed in the brains of these mice, which develop an impaired learning phenotype directly proportional to brain oAβ levels. Method: Male and female TgAPPE693Q mice and wildtype controls were compared using learning behavioral studies, immunocytochemistry, transmission electron microscopy, electrophysiology, protofibril‐specific assays, and single cell RNA sequencing. Result: Brain levels of nonfibrillar oAβ in Dutch mice were shown to increase aging‐dependently using A11 immunocytochemistry and FITC‐cyclic peptide (FITC‐CP‐2) microscopy. Two assays excluded the presence of protofibrils. Electrophysiological characterization of hippocampal synapses in Dutch and wildtype mice at ∼7 and ∼11 months revealed no change in basal excitatory transmission, consistent with normal density and morphology of mGluR2/3+ synapses in hippocampal CA1 of the same mice. One exception was increased postsynaptic density in non‐perforated mGluR‐2/3+ synapses in the Dutch mice. Functional characterization of the presynaptic terminal showed abnormalities in post‐tetanic potentiation, synaptic fatigue, and synaptic replenishment after depletion in Dutch mice. Single cell RNA‐seq to elucidate cell‐type specific transcriptional responses to oAβ revealed altered transcriptional profiles in multiple cell types. Unexpectedly, no obvious differences existed between profiles of microglia from Dutch compared to those from wildtype mice. Excitatory neurons showed the most altered profile which was associated with 'protein translation' and 'oxidative phosphorylation'. Ultrastructural analysis of presynaptic mitochondria at excitatory synapses revealed fewer mitochondria in the presynaptic terminals of Dutch mice. Conclusion: The profound learning behavior deficits in Dutch mice are associated with presynaptic functional deficits and mitochondrial abnormalities in excitatory neurons of the hippocampus. Nonfibrillar oAβ deposits were revealed by co‐localization of A11 immunoreactivity with FITC‐CP‐2 microscopy. Mice accumulating only oAβ may be especially useful for further characterization of the oligomer‐specific cyclic azaglycine PET tracer Lys (64Cu/NOTA)1]‐CP‐7 that shows robust PET signal from 44‐day‐old presymptomatic 5xFAD mice [Habashi, M. et al. Proc. Natl. Acad. Sci. U.S.A. 2022]. [ABSTRACT FROM AUTHOR]

Introduction: Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive., Methods: We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models., Results: HNK activated extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid-β oligomers (AβO)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice., Discussion: Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD., Highlights: The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways. HNK corrects hippocampal synaptic and memory defects in two mouse models of AD. Rescue of synaptic and memory impairments by HNK depends on ERK signaling. HNK corrects aberrant transcriptional signatures in APP/PS1 mice., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

After several years of research in the field of Alzheimer's disease (AD), it is still unclear how amyloid-beta (Aβ) and Tau, two key hallmarks of the disease, mediate the neuropathogenic events that lead to AD. Current data challenge the "Amyloid Cascade Hypothesis" that has prevailed in the field of AD, stating that Aβ precedes and triggers Tau pathology that will eventually become the toxic entity in the progression of the disease. This perspective also led the field of therapeutic approaches towards the development of strategies that target Aβ or Tau. In the present review, we discuss recent literature regarding the neurotoxic role of both Aβ and Tau in AD, as well as their physiological function in the healthy brain. Consequently, we present studies suggesting that Aβ and Tau act independently of each other in mediating neurotoxicity in AD, thereafter, re-evaluating the "Amyloid Cascade Hypothesis" that places Tau pathology downstream of Aβ. More recent studies have confirmed that both Aβ and Tau could propagate the disease and induce synaptic and memory impairments via the amyloid precursor protein (APP). This finding is not only interesting from a mechanistic point of view since it provides better insights into the AD pathogenesis but also from a therapeutic point of view since it renders APP a common downstream effector for both Aβ and Tau. Subsequently, therapeutic strategies that act on APP might provide a more viable and physiologically relevant approach for targeting AD.