Amyloid-β Induced Neuronal Dysfunction in Alzheimer’s Disease: From Synapses toward Neural Networks

By J. Palop, L. Mucke. Nature Neuroscience, 2010

1,766 citations recorded by the source corpus.

Alzheimer's disease is the most frequent neurodegenerative disorder and the most common cause of dementia in the elderly. Diverse lines of evidence suggest that amyloid-β (Aβ) peptides have a causal role in its pathogenesis, but the underlying mechanisms remain uncertain. Here we discuss recent evidence that Aβ may be part of a mechanism controlling synaptic activity, acting as a positive regulator presynaptically and a negative regulator postsynaptically. The pathological accumulation of oligomeric Aβ assemblies depresses excitatory transmission at the synaptic level, but also triggers aberrant patterns of neuronal circuit activity and epileptiform discharges at the network level. Aβ-induced dysfunction of inhibitory interneurons likely increases synchrony among excitatory principal cells and contributes to the destabilization of neuronal networks. Strategies that block these Aβ effects may prevent cognitive decline in Alzheimer's disease. Potential obstacles and next steps toward this goal are discussed.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Physiology

View Paper: https://www.semanticscholar.org/paper/f9ef370a183036d2aea4d886229253190950cd61

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. D. Holtzman
2. L. Mucke
3. Michael W. Weiner
4. Ashish Raj
5. Amy Kuceyeski
6. J. Palop
7. G. Bu
8. Cornelis J. Stam

In Cognitive Neuroscience

1. Philip Scheltens
2. D. Holtzman
3. Olaf Sporns
4. Cornelis J. Stam
5. Elisabeth C. W. van Straaten
6. L. Mucke
7. W. de Haan
8. Katherine K. Mott

In Physiology

1. D. Holtzman
2. L. Mucke
3. J. Palop
4. J. Herz
5. G. Bu
6. Michael W. Weiner
7. Ashish Raj
8. Amy Kuceyeski

Citations in the corpus

• The Glymphatic System – A Beginner's Guide (2015, neutral): “where activity of the neurons might lead to increased shedding making synapses a source of extracellular bamyloid [98].”
• Hallmarks of neurodegenerative diseases. (2023, positive): “Functional magnetic resonance imaging (fMRI), which assesses neuronal network connectivity, indicates early network dysfunction in NDDs. 64,75,79,87,90,118 Fluorodeoxyglucose-PET (FDG-PET) reveals decreased glucose metabolism in AD, in line with decreased neuronal function in the disease.”
• A Network Diffusion Model of Disease Progression in Dementia (2012, background): “First, there is a considerable diversity of published opinion on the etiology of neurode-generation (Saxena and Caroni, 2011) and the effect of individual misfolding proteins (Whitwell et al., 2009; Palop and Mucke, 2010; Frost et al., 2009b).”
• Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. (2012, background): “…mechanism by which accelerated spine loss, increased tau phosphorylation (Kocherhans et al. 2010), loss of network homeostasis (Palop et al. 2007; Palop and Mucke 2010), and earlier disease onset through loss of neuroprotective compensatory bandwidth (Korwek et al. 2009) can be readily explained.”
• Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model (2012, background): “Convulsive seizures, which occur more frequently in AD patients than in control populations, may represent the tip of an iceberg (3, 7).”