Amyloid β oligomers decrease hippocampal spontaneous network activity in an age-dependent manner

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Soluble amyloid beta (Abeta) oligomers are implicated in early Alzheimer's Disease (AD) cognitive decline.
• Previous research indicated Abeta(25-35) affects hippocampal slice activity at high nanomolar concentrations.

Purpose of the Study:

• To investigate the effects of oligomerized full-length Abeta(1-42) on CA1 hippocampal network activity.
• To determine if these effects are age-dependent.

Main Methods:

• Extracellular field recordings of spontaneous hippocampal network activity in slices.
• Dose-response analysis of oligomerized Abeta(1-42) (osAbeta).
• Assessment of age-related sensitivity to osAbeta.

Main Results:

• Oligomerized Abeta(1-42) potently inhibited spontaneous hippocampal network activity in a dose-dependent manner (IC(50) ≈ 0.4 nM, maximal effect at 10 nM).
• While basal network activity was age-independent, sensitivity to 10 nM osAbeta increased in older animals.
• Significant inhibition in young animals (second week) required 100 nM osAbeta, indicating age-dependent effects.
• osAbeta-induced inhibition was linked to presynaptic reductions in synaptic potentials and was specific, reversible, and not due to cell death.

Conclusions:

• Oligomerized Abeta(1-42) alters hippocampal network activity at AD-relevant concentrations.
• The inhibitory effect of osAbeta on hippocampal network activity is potentiated with age.
• These findings highlight a potential mechanism for age-related cognitive decline in AD.