Computational Study of Hippocampal-Septal Theta Rhythm Changes Due to Beta-Amyloid-Altered Ionic Channels

Electroencephagraphy (EEG) of many dementia patients has been characterized by an increase in low frequency field potential oscillations. One of the characteristics of early stage Alzheimer’s disease (AD) is an increase in theta band power (4–7 Hz). However, the mechanism(s) underlying the changes in theta oscillations are still unclear. To address this issue, we investigate the theta band power changes associated with β-Amyloid (Aβ) peptide (one of the main markers of AD) using a computational model, and by mediating the toxicity of hippocampal pyramidal neurons. We use an established biophysical hippocampal CA1-medial septum network model to evaluate four ionic channels in pyramidal neurons, which were demonstrated to be affected by Aβ. They are the L-type Ca2+ channel, delayed rectifying K+ channel, A-type fast-inactivating K+ channel and large-conductance Ca2+-activated K+ channel. Our simulation results demonstrate that only the Aβ inhibited A-type fast-inactivating K+ channel can induce an increase in hippocampo-septal theta band power, while the other channels do not affect theta rhythm. We further deduce that this increased theta band power is due to enhanced synchrony of the pyramidal neurons. Our research may elucidate potential biomarkers and therapeutics for AD. Further investigation will be helpful for better understanding of AD-induced theta rhythm abnormalities and associated cognitive deficits

Amyloid Beta Peptide Slows Down Sensory-Induced Hippocampal Oscillations

Alzheimer's disease (AD) progresses with a deterioration of hippocampal function that is likely induced by amyloid beta (Aβ) oligomers. Hippocampal function is strongly dependent on theta rhythm, and disruptions in this rhythm have been related to the reduction of cognitive performance in AD. Accordingly, both AD patients and AD-transgenic mice show an increase in theta rhythm at rest but a reduction in cognitive-induced theta rhythm. We have previously found that monomers of the short sequence of Aβ (peptide 25–35) reduce sensory-induced theta oscillations. However, considering on the one hand that different Aβ sequences differentially affect hippocampal oscillations and on the other hand that Aβ oligomers seem to be responsible for the cognitive decline observed in AD, here we aimed to explore the effect of Aβ oligomers on sensory-induced theta rhythm. Our results show that intracisternal injection of Aβ1–42 oligomers, which has no significant effect on spontaneous hippocampal activity, disrupts the induction of theta rhythm upon sensory stimulation. Instead of increasing the power in the theta band, the hippocampus of Aβ-treated animals responds to sensory stimulation (tail pinch) with an increase in lower frequencies. These findings demonstrate that Aβ alters induced theta rhythm, providing an in vivo model to test for therapeutic approaches to overcome Aβ-induced hippocampal and cognitive dysfunctions

Opportunities for multiscale computational modelling of serotonergic drug effects in Alzheimer’s disease

Alzheimer's disease (AD) is an age-specific neurodegenerative disease that compromises cognitive functioning and impacts the quality of life of an individual. Pathologically, AD is characterised by abnormal accumulation of beta-amyloid (A$\beta$) and hyperphosphorylated tau protein. Despite research advances over the last few decades, there is currently still no cure for AD. Although, medications are available to control some behavioural symptoms and slow the disease's progression, most prescribed medications are based on cholinesterase inhibitors. Over the last decade, there has been increased attention towards novel drugs, targeting alternative neurotransmitter pathways, particularly those targeting serotonergic (5-HT) system. In this review, we focused on 5-HT receptor (5-HTR) mediated signalling and drugs that target these receptors. These pathways regulate key proteins and kinases such as GSK-3 that are associated with abnormal levels of A$\beta$ and tau in AD. We then review computational studies related to 5-HT signalling pathways with the potential for providing deeper understanding of AD pathologies. In particular, we suggest that multiscale and multilevel modelling approaches could potentially provide new insights into AD mechanisms, and towards discovering novel 5-HTR based therapeutic targets.Comment: Accepted manuscript in Neuropharmacolog

Implication des recepteurs nicotiniques α7 dans les deficits mnesiques induits par des injections intra-hippocampiques de peptides amyloïdes-beta (1-42) chez la souris

Although Alzheimer’s disease (AD) has been considered as one of the major causesfor dementia, the mechanisms by which cognitive decline appear still remain unclear.However, amyloid-β peptides (Aβ) seem to play a central role in the appearance of memoryimpairments in the time course of the disease, inducing down-regulation of the cholinergicsystem which is associated with cognitive decline. Based on these observations, the role of α7nicotinic receptors (α7-nAChRs) which can interact with Aβ was widely studied withoutconsensus about the involvement of these receptors in memory deficits induced by Aβ.In order to improve our knowledge about the mechanisms involved in Aβ side effects,our work aims at identify the role of α7-nAChRs via behavioral and molecular approaches.Thus, we used a mice model based on injections of oligomeric assemblies of Aβo(1-42) (Aβo(1-42)) in the CA1 field of the dorsal hippocampus (dCA1) which is a brain structure stronglyinvolved in memory processes, precociously affected in the AD and with a high density of α7-nAChRs.The first part of this study was to develop and validate this animal model to studythe effects induced by Aβo(1-42) in the dCA1 by behavioral and molecular approaches. Weshow that repeated injections of Aβo(1-42) in the dCA1 induce a specific disruption of workingmemory 7 days after the last injection whereas spatial memory is spared. We also showed thatworking memory disturbance is associated with decreased activation / phosphorylation ofERK1 / 2 in the hippocampo-frontal and septo-hippocampal networks. These data allowed usto validate our experimental model to specifically study the impact of Aβo(1-42) into the dorsalhippocampus.In the second part, we focused on the role played by the α7- nAChRs receptors inmemory disturbances induced by Aβo(1-42). Our results show that (1) KOα7 mice do notexhibit working memory deficits consecutively to intra-dCA1 Aβo(1-42) injections, (2) thememory deficits and decreasing activation of ERK1/2 induced by Aβo(1-42) are offset bypharmacological treatments partial agonist and antagonist of α7-nAChRs receptors, (3)treatment with a full agonist of α7-nAChRs receptors does not prevent memory deficits .Given these results, the α7-nAChRs receptor appears to be essential to the development ofmemory deficits induced by Aβo(1-42), and the use of antagonists of these receptors might be apotential target for developing new therapeutic strategies for AD.Bien que la maladie d’Alzheimer (MA) soit la cause de démence la plus fréquente, lesmécanismes qui sous-tendent les déficits cognitifs chez les patients restent mal connus.Cependant, les peptides amyloïdes (Aβ) semblent être un acteur majeur impliqué dansl’apparition des troubles mnésiques au cours de l’évolution de la maladie, notamment de parleur capacité à induire un hypofonctionnement du système cholinergique associé au déclinmnésique. Sur la base de ces observations, le rôle joué par les récepteurs cholinergiquesnicotiniques α7 (α7-nAChRs) a été largement étudié, au vue de leur capacité à interagir avecles Aβ, sans toutefois dégager un consensus quant à l’implication de ces récepteurs dans lesdéficits mnésiques induits par les Aβ.Afin d’améliorer notre compréhension quant aux mécanismes sous-tendant les effetsdélétères induits par les Aβ dans les déficits mnésiques, notre travail visait à identifier le rôlejoué par les récepteurs α7-AChRs via une approche comportementale, pharmacologique etmoléculaire. Ainsi, nous avons utilisé un modèle « souris » basé sur des injections de formesoligomériques d’Aβ(1-42) (Aβo(1-42)) dans la région CA1 de l’hippocampe dorsal (dCA1),structure cérébrale impliquée dans les processus mnésiques, atteinte de manière précoce dansla MA et exprimant fortement les récepteurs α7-nAChRs.La première partie de cette étude a consisté à mettre au point et à valider notre modèleanimal d’étude des effets induits par les Aβo(1-42) dans le dCA1 par une approchecomportementale et moléculaire. Nous montrons que les injections répétées d’Aβo(1-42) dans ledCA1 induisent une perturbation spécifique de la mémoire de travail alors que la mémoirespatiale est préservée lorsque les performances mnésiques sont évaluées 7 jours après ladernière injection. Nous avons également montré que cette perturbation de la mémoire detravail est associée à une absence d’activation/phosphorylation de ERK1/2 au sein du réseauhippocampo-frontal et septo-hippocampique. Ces données nous ont permis de valider notremodèle expérimental permettant d’étudier spécifiquement l’impact des Aβo(1-42) dansl’hippocampe dorsal.Dans une seconde partie, nous nous sommes focalisés sur le rôle joué par lesrécepteurs α7-nAChRs dans les perturbations mnésiques induites par les Aβo(1-42). Nosrésultats montrent que (1) les souris KOα7 ne présentent pas de déficits de mémoire de travailconsécutivement aux injections intra-dCA1 d’Aβo(1-42), (2) les déficits mnésiques ainsi que lala perturbation de l’activation de ERK1/2 induits par les Aβo(1-42) sont compensés par destraitements pharmacologiques agoniste partiel et antagoniste des récepteurs α7-nAChRs, (3)le traitement par un agoniste complet des récepteurs α7-nAChRs ne permet pas de prévenir lesdéficits mnésiques. Au regard de ces résultats, le récepteur α7-nAChRs semble être essentielau développement des déficits mnésiques induits par les Aβo(1-42), et l’utilisationd’antagonistes de ces récepteurs pourraient être une cible potentielle pour le développementde nouvelles stratégies thérapeutiques

Neurocomputational models of Alzheimer’s disease

There have been a few attempts to design computational models of AD. Some of these models focus on hippocampus function yet many suffer from simulating exact effects of amyloid plaques and neurofibrillary tangles. See Duch (2007) for a review of some AD models. Below, we discuss biochemical, single cell, biophysical spiking, and systems-level and abstract models of AD

Assessing Alpha Band Event-related Synchronisation/Desynchronisation Using a Bio-Inspired Computational Model

This paper describes a study of the effects of variation of synaptic connectivity in a thalamo-cortical circuitry using a neural mass model. The oscillatory behaviour of the model output is assessed within the alpha frequency band. The model presented here is a modification of an existing model involving the introduction of biologically plausible synaptic connectivities as well as synaptic structure. Our goal is to study altered event related desynchronisation/synchronisation (ERD/ERS) patterns within the alpha band in Alzheimers disease as observed in experimental studies. ERD is an amplitude attenuation of certain EEG rhythms when an event is initiated or while a certain event is taking place in the brain. ERS is an amplitude enhancement of a certain EEG rhythm when cortical areas are not specifically engaged in a given mode of activity at a certain instant of time. EEG desynchronisation normally blocks alpha rhythms in the EEG due to sensory processing or behaviour. The results show that a decrease in synaptic connectivity induces a time lag in both ERD and ERS peaks in the model output. Furthermore, a deficiency induced in the inhibitory cholinergic pathway results in a distinct effect on time to peak in the ERD/ERS response. These observations are consistent with experimental findings in AD. Variation of the level of interconnectivity has a pronounced effect on the ERS behaviour of the model while the excitatory connectivity in the retino-geniculate pathway during the resting state is more influential on the ERD behaviour

Novel players in the aging synapse: impact on cognition

© Mariana Temido-Ferreira, et al. 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are cited.While neuronal loss has long been considered as the main contributor to age-related cognitive decline, these alterations are currently attributed to gradual synaptic dysfunction driven by calcium dyshomeostasis and alterations in ionotropic/metabotropic receptors. Given the key role of the hippocampus in encoding, storage, and retrieval of memory, the morpho- and electrophysiological alterations that occur in the major synapse of this network-the glutamatergic-deserve special attention. We guide you through the hippocampal anatomy, circuitry, and function in physiological context and focus on alterations in neuronal morphology, calcium dynamics, and plasticity induced by aging and Alzheimer's disease (AD). We provide state-of-the art knowledge on glutamatergic transmission and discuss implications of these novel players for intervention. A link between regular consumption of caffeine-an adenosine receptor blocker-to decreased risk of AD in humans is well established, while the mechanisms responsible have only now been uncovered. We review compelling evidence from humans and animal models that implicate adenosine A2A receptors (A2AR) upsurge as a crucial mediator of age-related synaptic dysfunction. The relevance of this mechanism in patients was very recently demonstrated in the form of a significant association of the A2AR-encoding gene with hippocampal volume (synaptic loss) in mild cognitive impairment and AD. Novel pathways implicate A2AR in the control of mGluR5-dependent NMDAR activation and subsequent Ca2+ dysfunction upon aging. The nature of this receptor makes it particularly suited for long-term therapies, as an alternative for regulating aberrant mGluR5/NMDAR signaling in aging and disease, without disrupting their crucial constitutive activity.M.T.-F. and J.E.C. were supported by a fellowship from Fundação para a Ciência e Tecnologia (FCT, Portugal); L.V.L is an Investigator CEEC-FCT. P.A.P. is supported by EU Joint Program—Neurodegenerative Disease Research (JPND) project CIRCPROT (jointly funded by BMBF, MIUR, and EU Horizon 2020 grant agreement no. 643417). This study was also funded by Santa Casa da Misericórdia - Mantero Belard 2018 (MB-7-2018) and by UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/ Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado.info:eu-repo/semantics/publishedVersio

POTENTIAL MECHANISMS OF HIPPOCAMPAL RESILIENCE TO ALZHEIMER’S DISEASE PATHOLOGY

Alzheimer’s disease (AD) is an age-related, progressive neurodegenerative proteinopathy with few treatments and no cure. Accumulation of beta amyloid and tau proteins are associated with disease symptoms including cognitive dysfunction and impaired spatial learning and memory. New therapeutic strategies are vital to address disease etiology and symptoms, but recent clinical failures have underscored the importance of mechanistic studies that search for new resilience factors in the context of disease progression. We define two possible mechanisms of neural resilience to AD symptoms and pathophysiology in the hippocampus, a nexus of spatial learning and memory and a critical site of synergy for amyloid and tau pathophysiology. These studies describe the interaction of two critical inhibitory neuron populations in the process of spatial learning and memory and detect early signs of dysfunction in a mouse model of AD. This work also identifies novel inhibitory circuit remodeling associated with stabilization of hippocampal activity alterations and indicates that inhibitory circuit fiber outgrowth in the hippocampus confers resilience to AD pathophysiology. Our results also establish disease relevance for an understudied innate waste clearance of the brain in both human AD patients and mouse models. This reserve waste clearance system relies on astrocytes to encase deleterious proteins and cellular organelles in dense, carbohydrate-rich structures termed corpora amylacea and periodic acid-Schiff granules in humans and mice, respectively. Our results indicate that tau can localize to these waste containers in the human and mouse hippocampus and that their generation is associated with increased astrocytic reactivity. We further describe the bimodal trajectory of hippocampal CA density in relation to advancing tau pathology (Braak 06) stage in AD patients and decreased hippocampal CA density in demented patients when compared to cognitively normal controls. Furthermore, we established relationships with CA density and advancing biological age, amyloid score, and APOE allele variant at select AD progression stages. These results indicate that loss of CA as a reserve waste clearance system is associated with poor cognitive outcomes and advanced Braak stage in a cohort of human AD patients. Overall, our studies highlight two possible resilience mechanisms for future targeted therapies in AD.Doctor of Philosoph