Faculty Opinions recommendation of Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease.

Abstract APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer’s disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.

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VAMP2 is a cerebrospinal fluid marker of selective hippocampal synapse loss and episodic memory performance in Alzheimer’s disease

Alzheimer s & Dementia ◽

10.1002/alz.045268 ◽

2020 ◽

Vol 16 (S4) ◽

Author(s):

Olivia Belbin ◽

Beatriu Molina ◽

Raúl Núñez‐Llaves ◽

Julie Goossens ◽

Nele Dewit ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Episodic Memory ◽

Memory Performance ◽

Synapse Loss

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Synapse loss in the temporal lobe in Alzheimer's disease

Annals of Neurology ◽

10.1002/ana.410330209 ◽

1993 ◽

Vol 33 (2) ◽

pp. 190-199 ◽

Cited By ~ 147

Author(s):

Scheff W. Scheff ◽

Douglas A. Price

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Synapse Loss

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Inhibitory synapse loss and accumulation of amyloid beta in inhibitory presynaptic terminals in Alzheimer’s disease

European Journal of Neurology ◽

10.1111/ene.15043 ◽

2021 ◽

Author(s):

Hatice Kurucu ◽

Martí Colom‐Cadena ◽

Caitlin Davies ◽

Lewis Wilkins ◽

Declan King ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Inhibitory Synapse ◽

Presynaptic Terminals ◽

Synapse Loss

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Faculty Opinions recommendation of Noncanonical transnitrosylation network contributes to synapse loss in Alzheimer's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.739149169.793582963 ◽

2021 ◽

Author(s):

Angus Nairn ◽

Shannon Leslie

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synapse Loss

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Human tau filaments induce microtubule and synapse loss in an in vivo model of neurofibrillary degenerative disease

Journal of Cell Science ◽

10.1242/jcs.113.8.1373 ◽

2000 ◽

Vol 113 (8) ◽

pp. 1373-1387 ◽

Cited By ~ 1

Author(s):

G.F. Hall ◽

B. Chu ◽

G. Lee ◽

J. Yao

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Intracellular Transport ◽

Degenerative Disease ◽

In Vivo Model ◽

Filament Formation ◽

Synapse Loss ◽

Central Neurons ◽

Cytoskeletal Disruption

The intracellular accumulation of tau protein and its aggregation into filamentous deposits is the intracellular hallmark of neurofibrillary degenerative diseases such as Alzheimer's Disease and familial tauopathies in which tau is now thought to play a critical pathogenic role. Until very recently, the lack of a cellular model in which human tau filaments can be experimentally generated has prevented direct investigation of the causes and consequences of tau filament formation in vivo. In this study, we show that human tau filaments formed in lamprey central neurons (ABCs) that chronically overexpress human tau resemble the ‘straight filaments’ seen in Alzheimer's Disease and other neurofibrillary conditions, and are distinguishable from neurofilaments by their ultrastructure, distribution and intracellular behavior. We also show that tau filament formation in ABCs is associated with a distinctive pattern of dendritic degeneration that closely resembles the cytopathology of human neurofibrillary degenerative disease. This pattern includes localized cytoskeletal disruption and aggregation of membranous organelles, distal dendritic beading, and the progressive loss of dendritic microtubules and synapses. These results suggest that tau filament formation may be responsible for many key cytopathological features of neurofibrillary degeneration, possibly via the loss of microtubule based intracellular transport.

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Stimulation-Dependent Intraspinal Microtubules and Synaptic Failure in Alzheimer's Disease: A Review

International Journal of Alzheimer s Disease ◽

10.1155/2012/519682 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Fuyuki Mitsuyama ◽

Yoshio Futatsugi ◽

Masato Okuya ◽

Tsukasa Kawase ◽

Kostadin Karagiozov ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Structural Change ◽

Cognitive Deficits ◽

Postsynaptic Membrane ◽

Structural Mechanism ◽

Synapse Loss ◽

Synaptic Failure

There are many microtubules in axons and dendritic shafts, but it has been thought that there were fewer microtubules in spines. Recently, there have been four reports that observed the intraspinal microtubules. Because microtubules originate from the centrosome, these four reports strongly suggest a stimulation-dependent connection between the nucleus and the stimulated postsynaptic membrane by microtubules. In contrast, several pieces of evidence suggest that spine elongation may be caused by the polymerization of intraspinal microtubules. This structural mechanism for spine elongation suggests, conversely, that the synapse loss or spine loss observed in Alzheimer’s disease may be caused by the depolymerization of intraspinal microtubules. Based on this evidence, it is suggested that the impairment of intraspinal microtubules may cause spinal structural change and block the translocation of plasticity-related molecules between the stimulated postsynaptic membranes and the nucleus, resulting in the cognitive deficits of Alzheimer's disease.

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E4 allele dosage does not predict cholinergic activity or synapse loss in Alzheimer's disease

Neurology ◽

10.1212/wnl.54.2.403 ◽

2000 ◽

Vol 54 (2) ◽

pp. 403-403 ◽

Cited By ~ 26

Author(s):

J. Corey-Bloom ◽

P. Tiraboschi ◽

L. A. Hansen ◽

M. Alford ◽

B. Schoos ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cholinergic Activity ◽

Synapse Loss ◽

Allele Dosage ◽

E4 Allele

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Computer Model of Synapse Loss During an Alzheimer’s Disease-like Pathology in Hippocampal Subregions DG, CA3 and CA1—the Way to Chaos and Information Transfer

Entropy ◽

10.3390/e21040408 ◽

2019 ◽

Vol 21 (4) ◽

pp. 408 ◽

Cited By ~ 3

Author(s):

Świetlik ◽

Białowąs ◽

Moryś ◽

Kusiak

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lyapunov Exponent ◽

Information Flow ◽

Shannon Entropy ◽

Control Model ◽

Maximal Lyapunov Exponent ◽

Synapse Loss ◽

Entropy Transfer ◽

Pathological Model

The aim of the study was to compare the computer model of synaptic breakdown in an Alzheimer’s disease-like pathology in the dentate gyrus (DG), CA3 and CA1 regions of the hippocampus with a control model using neuronal parameters and methods describing the complexity of the system, such as the correlative dimension, Shannon entropy and positive maximal Lyapunov exponent. The model of synaptic breakdown (from 13% to 50%) in the hippocampus modeling the dynamics of an Alzheimer’s disease-like pathology was simulated. Modeling consisted in turning off one after the other EC2 connections and connections from the dentate gyrus on the CA3 pyramidal neurons. The pathological model of synaptic disintegration was compared to a control. The larger synaptic breakdown was associated with a statistically significant decrease in the number of spikes (R = −0.79, P < 0.001), spikes per burst (R = −0.76, P < 0.001) and burst duration (R = −0.83, P < 0.001) and an increase in the inter-burst interval (R = 0.85, P < 0.001) in DG-CA3-CA1. The positive maximal Lyapunov exponent in the control model was negative, but in the pathological model had a positive value of DG-CA3-CA1. A statistically significant decrease of Shannon entropy with the direction of information flow DG->CA3->CA1 (R = −0.79, P < 0.001) in the pathological model and a statistically significant increase with greater synaptic breakdown (R = 0.24, P < 0.05) of the CA3-CA1 region was obtained. The reduction of entropy transfer for DG->CA3 at the level of synaptic breakdown of 35% was 35%, compared with the control. Entropy transfer for CA3->CA1 at the level of synaptic breakdown of 35% increased to 95% relative to the control. The synaptic breakdown model in an Alzheimer’s disease-like pathology in DG-CA3-CA1 exhibits chaotic features as opposed to the control. Synaptic breakdown in which an increase of Shannon entropy is observed indicates an irreversible process of Alzheimer’s disease. The increase in synapse loss resulted in decreased information flow and entropy transfer in DG->CA3, and at the same time a strong increase in CA3->CA1.

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