Stabilized Low-n Amyloid-ß Oligomers Induce Robust Novel Object Recognition Deficits Associated with Inflammatory, Synaptic, and GABAergic Dysfunction in the Rat.
J Alzheimers Dis
; 62(1): 213-226, 2018.
Article
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| MEDLINE
| ID: mdl-29439327
ABSTRACT
BACKGROUND:
With current treatments for Alzheimer's disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-ß oligomers (Aßo). These small soluble Aßo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies.OBJECTIVE:
The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-ß1-42 oligomers (Aßo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat.METHODS:
Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aßo1-42 (10µL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1ß, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus).RESULTS:
Acute ICV administration of Aßo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss.CONCLUSION:
Taken together the results suggest that acute administration of soluble low-n Aßo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
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Péptidos beta-Amiloides
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Cognición
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Ácido gamma-Aminobutírico
/
Inflamación
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Trastornos de la Memoria
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Neuronas
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
J Alzheimers Dis
Asunto de la revista:
GERIATRIA
/
NEUROLOGIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Reino Unido