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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]

BACKGROUND: Background: Neurodegenerative diseases manifest behavioral dysfunction with disease progression. Intervention with neuropsychiatric drugs is part of most multi-drug treatment paradigms. However, only a fraction of patients responds to the treatments and those responding must deal with drug-drug interactions and tolerance issues generally attributed to off-target activities. Recent efforts have focused on the identification of underexplored targets and exploration of improved outcomes by treatment with selective molecular probes. Objective: As part of ongoing efforts to identify and validate additional targets amenable to therapeutic intervention, we examined levels of the serotonin 5-HT2b receptor (5-HT2bR) in Alzheimer's disease (AD) brains and the potential of a selective 5-HT2bR antagonist to counteract synaptic plasticity and memory damage induced by AD-related proteins, amyloid-β, and tau. Methods: This work used a combination of biochemical, chemical biology, electrophysiological, and behavioral techniques. Biochemical methods included analysis of protein levels. Chemical biology methods included the use of an in vivo molecular probe MW071, a selective antagonist for the 5HT2bR. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated spatial memory and associative memory. Results: 5HT2bR levels are increased in brain specimens of AD patients compared to controls. 5HT2bR antagonist treatment rescued amyloid-β and tau oligomer-induced impairment of synaptic plasticity and memory. Conclusions: The increased levels of 5HT-2bR in AD patient brains and the attenuation of disease-related synaptic and behavioral dysfunctions by MW071 treatment suggest that the 5HT-2bR is a molecular target worth pursuing as a potential therapeutic target. [ABSTRACT FROM AUTHOR]

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]

The amyloid hypothesis posits that the amyloid-beta (Aβ) 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 Aβ 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 Aβ-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 Aβ and tau together are more suitable to combat AD than therapies against one or the other alone. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a gaseous molecule that plays a multifactorial role in several cellular processes. In the central nervous system, the NO dual nature in neuroprotection and neurotoxicity has been explored to unveil its involvement in Alzheimer's disease (AD). A growing body of research shows that the activation of the NO signaling pathway leading to the phosphorylation of the transcription factor cyclic adenine monophosphate responsive element binding protein (CREB) (so-called NO/cGMP/PKG/CREB signaling pathway) ameliorates altered neuroplasticity and memory deficits in AD animal models. In addition to NO donors, several other pharmacological agents, such as phosphodiesterase 5 (PDE5) inhibitors have been used to activate the pathway and rescue memory disorders. PDE5 inhibitors, including sildenafil, tadalafil and vardenafil, are marketed for the treatment of erectile dysfunction and arterial pulmonary hypertension due to their vasodilatory properties. The ability of PDE5 inhibitors to interfere with the NO/cGMP/PKG/CREB signaling pathway by increasing the levels of cGMP has prompted the hypothesis that PDE5 inhibition might be used as an effective therapeutic strategy for the treatment of AD. To this end, newly designed PDE5 inhibitors belonging to different chemical classes with improved pharmacologic profile (e.g. higher potency, improved selectivity, and blood-brain barrier penetration) have been synthesized and evaluated in several animal models of AD. In addition, recent medicinal chemistry effort has led to the development of agents concurrently acting on the PDE5 enzyme and a second target involved in AD. Both marketed and investigational PDE5 inhibitors have shown to reverse cognitive defects in young and aged wild type mice as well as transgenic mouse models of AD and tauopathy using a variety of behavioral tasks. These studies confirmed the therapeutic potential of PDE5 inhibitors as cognitive enhancers. However, clinical studies assessing cognitive functions using marketed PDE5 inhibitors have not been conclusive. Drug discovery efforts by our group and others are currently directed towards the development of novel PDE5 inhibitors tailored to AD with improved pharmacodynamic and pharmacokinetic properties. In summary, the present perspective reports an overview of the correlation between the NO signaling and AD, as well as an outline of the PDE5 inhibitors used as an alternative approach in altering the NO pathway leading to an improvement of learning and memory. The last two sections describe the preclinical and clinical evaluation of PDE5 inhibitors for the treatment of AD, providing a comprehensive analysis of the current status of the AD drug discovery efforts involving PDE5 as a new therapeutic target. [ABSTRACT FROM AUTHOR]