Dopamine, sleep, and neuronal excitability modulate amyloid-β–mediated forgetting in Drosophila

Alzheimer disease (AD) is one of the main causes of age-related dementia and neurodegeneration. However, the onset of the disease and the mechanisms causing cognitive defects are not well understood. Aggregation of amyloidogenic peptides is a pathological hallmark of AD and is assumed to be a central component of the molecular disease pathways. Pan-neuronal expression of Aβ42Arctic peptides in Drosophila melanogaster results in learning and memory defects. Surprisingly, targeted expression to the mushroom bodies, a center for olfactory memories in the fly brain, does not interfere with learning but accelerates forgetting. We show here that reducing neuronal excitability either by feeding Levetiracetam or silencing of neurons in the involved circuitry ameliorates the phenotype. Furthermore, inhibition of the Rac-regulated forgetting pathway could rescue the Aβ42Arctic-mediated accelerated forgetting phenotype. Similar effects are achieved by increasing sleep, a critical regulator of neuronal homeostasis. Our results provide a functional framework connecting forgetting signaling and sleep, which are critical for regulating neuronal excitability and homeostasis and are therefore a promising mechanism to modulate forgetting caused by toxic Aβ peptides.

A centronuclear myopathy-causing mutation in dynamin-2 perturbs the actin-dependent structure of dendritic spines leading to excitatory synaptic defects in a murine model of the disease

Dynamin-2 is a large GTP-ase, member of the dynamin superfamily, that regulates membrane remodeling and cytoskeleton dynamics. In the mammalian nervous system dynamin-2 modulates synaptic vesicle (SV)-recycling at the nerve terminals and receptor-trafficking to and from postsynaptic densities (PSDs). Mutations in dynamin-2 cause autosomal dominant centronuclear myopathy (CNM), a congenital neuromuscular disorder characterized by progressive weakness and atrophy of distal skeletal muscles. Cognitive defects have also been reported in dynamin-2-linked CNM patients suggesting a concomitant impairment of the central nervous system. Here we addressed the mechanisms that lead to cognitive defects in dynamin-2-linked CNM using a knock-in mouse model that harbors the p.R465W mutation in dynamin-2, the most common causing CNM. Our results show that these mice exhibit reduced capability to learn and acquire spatial and recognition memory, impaired long-term potentiation of the excitatory synaptic strength and perturbed dendritic spine morphology, which seem to be associated with actin defects. Together, these data reveal for the first time that structural and functional synaptic defects underlie cognitive defects in the CNM context. In addition our results contribute to the still scarce knowledge about the importance of dynamin-2 at central synapses.

Memantine ameliorates cognitive deficit in AD mice via enhancement of entorhinal–CA1 projection

Background Memantine, a low- to moderate-affinity uncompetitive N-methyl-D-aspartate receptor antagonist, has been shown to improve cognitive functions in animal models of Alzheimer’s disease (AD). Here we treated APP/PS1 AD mice with a therapeutic dose of memantine (20 mg/kg/day) and examined its underlying mechanisms in ameliorating cognitive defects. Methods Using behavioral, electrophysiological, optogenetic and morphology approaches to explore how memantine delay the pathogenesis of AD. Results Memantine significantly improved the acquisition in Morris water maze (MWM) in APP/PS1 mice without affecting the speed of swimming. Furthermore, memantine enhanced EC to CA1 synaptic neurotransmission and promoted dendritic spine regeneration of EC neurons that projected to CA1. Conclusions Our study reveals the underlying mechanism of memantine in the treatment of AD mice.

Aminopeptidase A contributes to biochemical, anatomical and cognitive defects in Alzheimer’s disease (AD) mouse model and is increased at early stage in sporadic AD brain

One of the main components of senile plaques in Alzheimer’s disease (AD)-affected brain is the Aβ peptide species harboring a pyroglutamate at position three pE3-Aβ. Several studies indicated that pE3-Aβ is toxic, prone to aggregation and serves as a seed of Aβ aggregation. The cyclisation of the glutamate residue is produced by glutaminyl cyclase, the pharmacological and genetic reductions of which significantly alleviate AD-related anatomical lesions and cognitive defects in mice models. The cyclisation of the glutamate in position 3 requires prior removal of the Aβ N-terminal aspartyl residue to allow subsequent biotransformation. The enzyme responsible for this rate-limiting catalytic step and its relevance as a putative trigger of AD pathology remained yet to be established. Here, we identify aminopeptidase A as the main exopeptidase involved in the N-terminal truncation of Aβ and document its key contribution to AD-related anatomical and behavioral defects. First, we show by mass spectrometry that human recombinant aminopeptidase A (APA) truncates synthetic Aβ1-40 to yield Aβ2-40. We demonstrate that the pharmacological blockade of APA with its selective inhibitor RB150 restores the density of mature spines and significantly reduced filopodia-like processes in hippocampal organotypic slices cultures virally transduced with the Swedish mutated Aβ-precursor protein (βAPP). Pharmacological reduction of APA activity and lowering of its expression by shRNA affect pE3-42Aβ- and Aβ1-42-positive plaques and expressions in 3xTg-AD mice brains. Further, we show that both APA inhibitors and shRNA partly alleviate learning and memory deficits observed in 3xTg-AD mice. Importantly, we demonstrate that, concomitantly to the occurrence of pE3-42Aβ-positive plaques, APA activity is augmented at early Braak stages in sporadic AD brains. Overall, our data indicate that APA is a key enzyme involved in Aβ N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with AD pathology.

Behavioural and emotional aspects of Huntington’s disease

This chapter focuses on the behavioural and emotional aspects together with problems relating to thinking (cognitive defects). In many ways, these problems are often more difficult to manage for the families than the physical problems described in the previous chapter. Some of the issues discussed include: lack of perception of the needs of others; depression, apathy, and anxiety; difficulty planning ahead and changing plans in the light of new information; outbursts of temper; preoccupations or perseveration. There is a discussion of how a carer may have to change or adapt in order to avoid some of these problems. Some of the drugs used to help with the behavioural problems are the same as the ones used to treat the physical problems.

Balint-Holmes Syndrome due to stroke following SARS-CoV-2 infection: a single case report

In the present case report we describe the clinical features of a patient showing Balint-Holmes’ syndrome following bilateral parieto-occipital damage due to a stroke after SARS-CoV-2 infection. During neuropsychological assessment, the patient demonstrated severe optic ataxia, simulatanagnosia and gaze apraxia, which represent pathognomonic signs of Balint-Holmes’ syndrome. As several studies demonstrated that SARS-CoV-2 infection can affect the central nervous system, especially in presence of specific risks factors and neurological symptoms such as ageusia and anosmia, we considered the infection as a likely causal factor in our patient. Notwithstanding the association between SARS-CoV-2 infection and stroke has not been fully comprehended, our report contributes to raising attention on the possibility that it can lead to even quite rare cognitive defects.

Predictors of Cognitive Defects and Its Prevention Capabilities in Premature Infants

The article summarizes the materials of modern publications on cognitive development of premature infants in connection with perinatal factors and parenting conditions. Leading risk predictors of cognitive defects in premature infants are severe dysmaturity by the time of birth (gestational age <27 weeks) and need for intensive care during the first weeks of life. The data of longitudinal researches of the premature infants’ development until reaching their adulthood is presented. The structure of cognitive defects in this population is studied. The most common problems were revealed in learning mathematics, operational memory and purposeful behavior and activity. Frequency of these cognitive defects is associated with both: stage of prematurity social problems of the family. Modern neurovisualization methods (diffusion weighted imaging and functional magnetic resonance imaging (MRI) of the brain) allows to identify the defects in child nervous system (Connectome) development already at the age of 18 months. It can be the substrate of cognitive defects, and it will allow to predict individual development pathway and implement direct corrections and interventions.