Evidence that Alzheimer's Disease Is a Disease of Competitive Synaptic Plasticity Gone Awry.
J Alzheimers Dis
; 99(2): 447-470, 2024.
Article
em En
| MEDLINE
| ID: mdl-38669548
ABSTRACT
Mounting evidence indicates that a physiological function of amyloid-ß (Aß) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized the lines of evidence supporting this hypothesis and highlighted the similarities between Aß and anti-microbial peptides in mediating cell/synapse competition. In cell competition, anti-microbial peptides deploy a multitude of mechanisms to ensure both self-protection and competitor elimination. Here I review recent studies showing that similar mechanisms are at play in Aß-mediated synapse competition and perturbations in these mechanisms underpin Alzheimer's disease (AD). Specifically, I discuss evidence that Aß and ApoE, two crucial players in AD, co-operate in the regulation of synapse competition. Glial ApoE promotes self-protection by increasing the production of trophic monomeric Aß and inhibiting its assembly into toxic oligomers. Conversely, Aß oligomers, once assembled, promote the elimination of competitor synapses via direct toxic activity and amplification of "eat-me" signals promoting the elimination of weak synapses. I further summarize evidence that neuronal ApoE may be part of a gene regulatory network that normally promotes competitive plasticity, explaining the selective vulnerability of ApoE expressing neurons in AD brains. Lastly, I discuss evidence that sleep may be key to Aß-orchestrated plasticity, in which sleep is not only induced by Aß but is also required for Aß-mediated plasticity, underlining the link between sleep and AD. Together, these results strongly argue that AD is a disease of competitive synaptic plasticity gone awry, a novel perspective that may promote AD research.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sinapses
/
Peptídeos beta-Amiloides
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Doença de Alzheimer
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Plasticidade Neuronal
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Alzheimers Dis
Ano de publicação:
2024
Tipo de documento:
Article