Early signs of hippocampal network impairment in Alzheimer’s rat model revealed

Published on March 22, 2023

Imagine you’re baking a cake and you notice one ingredient is off. It might not ruin the entire cake, but it affects the overall taste. In a similar way, Alzheimer’s disease (AD) is caused by a buildup of toxic proteins that eventually leads to dementia. But what if we could catch these early signs of impairment before they become apparent? Well, scientists have discovered that changes in brain activity, specifically altered theta-gamma coupling and sharp wave-ripple, could be indications of early hippocampal network dysfunction in AD. By studying rats with a genetic predisposition to AD, researchers were able to identify these alterations in oscillatory activity at the pre-plaque stage. These findings suggest that targeting synaptic dysfunction at this early stage could be a potential therapeutic approach for AD. And by examining the properties of the altered brain activity, scientists gain valuable insights into the cognitive decline experienced in AD. So, if you’re curious to learn more about how alterations in brain activity can offer clues about early-stage AD, don’t forget to explore the full research article!

Alzheimer’s disease (AD) is a severe neurodegenerative disorder caused by the accumulation of toxic proteins, amyloid-beta (Aβ) and tau, which eventually leads to dementia. Disease-modifying therapies are still lacking, due to incomplete insights into the neuropathological mechanisms of AD. Synaptic dysfunction is known to occur before cognitive symptoms become apparent and recent studies have demonstrated that imbalanced synaptic signaling drives the progression of AD, suggesting that early synaptic dysfunction could be an interesting therapeutic target. Synaptic dysfunction results in altered oscillatory activity, which can be detected with electroencephalography and electrophysiological recordings. However, the majority of these studies have been performed at advanced stages of AD, when extensive damage and cognitive symptoms are already present. The current study aimed to investigate if the hippocampal oscillatory activity is altered at pre-plaque stages of AD. The rats received stereotactic surgery to implant a laminar electrode in the CA1 layer of the right hippocampus. Electrophysiological recordings during two consecutive days in an open field were performed in 4–5-month-old TgF344-AD rats when increased concentrations of soluble Aβ species were observed in the brain, in the absence of Aβ-plaques. We observed a decreased power of high theta oscillations in TgF344-AD rats compared to wild-type littermates. Sharp wave-ripple (SWR) analysis revealed an increased SWR power and a decreased duration of SWR during quiet wake in TgF344-AD rats. The alterations in properties of SWR and the increased power of fast oscillations are suggestive of neuronal hyperexcitability, as has been demonstrated to occur during presymptomatic stages of AD. In addition, decreased strength of theta-gamma coupling, an important neuronal correlate of memory encoding, was observed in the TgF344-AD rats. Theta-gamma phase amplitude coupling has been associated with memory encoding and the execution of cognitive functions. Studies have demonstrated that mild cognitive impairment patients display decreased coupling strength, similar to what is described here. The current study demonstrates altered hippocampal network activity occurring at pre-plaque stages of AD and provides insights into prodromal network dysfunction in AD. The alterations observed could aid in the detection of AD during presymptomatic stages.

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