Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer’s Disease

Miranda, André; Herman, Mathieu; Cheng, Rong; Nahmani, Eden; Barrett, Geoffrey M.; Micevska, Elizabeta; Fontaine, G.; Potier, Marie‐Claude; Head, Elizabeth; Schmitt, Frederick A.; Lott, Ira T.; Jiménez‐Velázquez, Ivonne Z.; Antonarakis, Stylianos E.; Paolo, Gilbert Di; Lee, Joseph H.; Hussaini, S. Abid; Marquer, Catherine

doi:10.1016/j.celrep.2018.05.011

Cited by 46 publications

(37 citation statements)

References 58 publications

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“…Thus, the observation of endosomal proteins by fluorescence staining using confocal microscopy can only reveal puncta-like signals, corresponding to protein microdomains at the endosomal surface. This aspect is critical, because it implies that confocal microscopy observations rather relate to the morphology of endosomal protein microdomains rather than to the global early endosomal morphology, especially when early endosomes are large enough for microdomains to be visible [33,57,58,63]. Experiments resulting in the enlargement of early endosomes, achieved via transfection of Rab5-Q79L, clearly show the clusters of high intensity of endosomal proteins, such as EEA1, at the endosomal limiting membrane [33,55,63,64].…”

Section: Early Endosomes Morphology In Ds Studied At Highresolutionmentioning

confidence: 99%

Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome

Botté

Lainé

Xicota

et al. 2020

acta neuropathol commun

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Enlarged early endosomes have been visualized in Alzheimer's disease (AD) and Down syndrome (DS) using conventional confocal microscopy at a resolution corresponding to endosomal size (hundreds of nm). In order to overtake the diffraction limit, we used super-resolution structured illumination microscopy (SR-SIM) and transmission electron microscopies (TEM) to analyze the early endosomal compartment in DS. By immunofluorescence and confocal microscopy, we confirmed that the volume of Early Endosome Antigen 1 (EEA1)-positive puncta was 13-19% larger in fibroblasts and iPSC-derived neurons from individuals with DS, and in basal forebrain cholinergic neurons (BFCN) of the Ts65Dn mice modelling DS. However, EEA1-positive structures imaged by TEM or SR-SIM after chemical fixation had a normal size but appeared clustered. In order to disentangle these discrepancies, we imaged optimally preserved High Pressure Freezing (HPF)-vitrified DS fibroblasts by TEM and found that early endosomes were 75% denser but remained normal-sized. RNA sequencing of DS and euploid fibroblasts revealed a subgroup of differentially-expressed genes related to cargo sorting at multivesicular bodies (MVBs). We thus studied the dynamics of endocytosis, recycling and MVBdependent degradation in DS fibroblasts. We found no change in endocytosis, increased recycling and delayed degradation, suggesting a "traffic jam" in the endosomal compartment. Finally, we show that the phosphoinositide PI (3) P, involved in early endosome fusion, is decreased in DS fibroblasts, unveiling a new mechanism for endosomal dysfunctions in DS and a target for pharmacotherapy.

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Section: Early Endosomes Morphology In Ds Studied At Highresolutionmentioning

confidence: 99%

Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome

Botté

Lainé

Xicota

et al. 2020

acta neuropathol commun

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“…When both excitatory and inhibitory synapses were affected, the resolution and stability of the place map were significantly diminished, accompanied by increased neuronal activity. This combination of dysfunctions has also been detected in an APP transgenic model [25], and in a mouse model overexpressing synaptojanin-1 (Synj1), a regulator of synaptic function, which has been implicated in AD [95, 96]. This provides further support for synaptic dysfunction underlying place cell abnormalities and suggests that both excitatory and inhibitory synaptic dysfunction contribute to place cell dysfunction in AD and produce distinct impairments in environmental representation.…”

Section: Discussionmentioning

confidence: 76%

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease

Ness

Schultz

2020

Preprint

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Alzheimer’s Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution.Author SummaryCognitive decline in Alzheimer’s Disease (AD) correlates most strongly with dysfunction and loss of synapses in affected brain regions. While synaptic dysfunction is a well-established early symptom of AD, how impaired synaptic transmission may lead to progressive cognitive decline, remains subject to active research. In this study, we examine the effect of synapse loss on neuronal network function using a computational model of place cells in the hippocampal network. Place cells encode a cognitive map of an animal’s environment, enabling navigation and spatial memory. This provides a useful indicator of cognitive function, as place cell function is well characterized and abnormalities in place cell firing have been shown to underlie navigational deficits in rodents. We find that synapse loss in our network is sufficient to produce progressive impairments in place cell function, which resemble those observed in mouse models of the disease, supporting the hypothesis that synaptic dysfunction may underlie the cognitive impairment in AD. Furthermore, we observe that loss of excitatory and inhibitory synapses produce distinct spatial impairments. Future experiments investigating the relative contribution of different synaptic inputs may thus allow new insights into the neuronal network alterations in AD and potentially enable the identification of new therapeutic targets.

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“…Various (Byrne et al, 1996;Byrne et al, 1998) TPD54 125853 (Nguyen et al, 2019) 2010), bridging integrator 1 (BIN1)/amphiphysin 2 (Hu et al, 2011;Seshadri et al, 2010), cortactin-CD2-associated protein (CD2AP) (Hollingworth et al, 2011;Naj et al, 2011) and synaptojanin (McMahon and Boucrot, 2011;Miranda et al, 2018), with the risk of acquiring Alzheimer's disease (AD). Additionally, deficiency in VPS26 and VPS35, two subunits of the retromer complex for endosomal recycling, has been observed in AD (Small et al, 2005).…”

Section: Membrane Fusion Snare Binding Proteinmentioning

confidence: 99%

Membrane trafficking in health and disease

Yarwood

Hellicar

Woodman

et al. 2020

Disease Models &Amp; Mechanisms

111

107

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Membrane trafficking pathways are essential for the viability and growth of cells, and play a major role in the interaction of cells with their environment. In this At a Glance article and accompanying poster, we outline the major cellular trafficking pathways and discuss how defects in the function of the molecular machinery that mediates this transport lead to various diseases in humans. We also briefly discuss possible therapeutic approaches that may be used in the future treatment of trafficking-based disorders.

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Excess Synaptojanin 1 Contributes to Place Cell Dysfunction and Memory Deficits in the Aging Hippocampus in Three Types of Alzheimer’s Disease

Cited by 46 publications

References 58 publications

Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome

Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome

A computational grid-to-place-cell transformation model indicates a synaptic driver of place cell impairment in early-stage Alzheimer’s Disease

Membrane trafficking in health and disease

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