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Can Alzheimer’s Memory Impairments Be Rescued?


– PhD

Affiliations : The Douglas Institute, McGill, Canada

Journal reference: DOI: 10.1038/s41467-019-13260-9

Summary: In this article, Dr. Etter explains the alterations in brain waves of Alzheimer patients. The alterations precede neuronal death and could serve as a potential biomarker to improve diagnoses.

Currently, 50 million people are suffering from Alzheimer’s disease (AD) throughout the world. Considering the gradual ageing of the world population, this number should increase to 152 million by 2050. To this date, there is no cure for AD and the exact mechanisms of the disease are still poorly understood. The brain of AD patients usually displays the presence of a viscous protein named amyloid beta, that aggregates and ends up forming plaques, leading to subsequent neuronal death. Consequently, most efforts in AD research have focused on reducing the presence of amyloid beta (with the use of  antibodies, most notably). So far, these approaches have not been particularly effective and numerous observations suggest that this might not be the best strategy in treating AD. In particular, mild cognitive impairments that can predict the onset of AD pathology, usually occur long before any observable neuronal death or amyloid beta deposits. On the other hand, several studies done in humans and rodents have shown that these mild cognitive impairments are associated with drastic changes in brain oscillations, which could thus provide a good diagnostic of AD progression. 

Brain oscillations reflect the rhythmic activity of large groups of neurons that are sequentially activated, and thus are believed to indirectly reflect cognitive processes. In particular, oscillations in the gamma band (30-120 Hz) were shown to be particularly prominent during memory encoding and retrieval in humans, non-human primates and rodents. What if defects in oscillatory patterns were at the origin of AD pathology, long before plaques and neuronal death? This is exactly the hypothesis that we tested in our recent study published last year in Nature Communications. 

Brain oscillations are known to be controlled by a specific class of neurons called ‘inhibitory interneurons’. Previous studies have shown that using deep brain electrical stimulations, brain rhythms can be entrained by using high frequency electrical stimulation. However one of the major caveats of electrical stimulations is that it targets a wide array of non specific groups of neurons, leading to unwanted side effects. In a sense, these electrical stimulations can be seen as literally applying electroshocks inside the brain.

To remedy this, we used optogenetics, a technique that consists of genetically re-engineering inhibitory interneurons specifically so that they can be activated by light. We found that using this technique, we were able to control brain rhythms within a wide range of frequencies, and with minimal side effects since we only targeted inhibitory interneurons. More importantly, using optogenetic stimulations we could ‘boost’ brain oscillations in the gamma range, that is known to be essential for memory processing. 

To test whether gamma oscillations play a major role in AD, we worked with an AD mouse model. Mice do not spontaneously develop AD, so we used a mutant mouse that expressed the amyloid beta when adult. We trained these mice in a novel object task, where we assess their memory performance by measuring the amount of time spent with a novel versus familiar object. Provided they remember which object they have previously explored, they should spend more time with the novel object. In our AD mice, we observed that they explored both familiar and novel objects to a similar extent, indicating that they might not remember previous exposures to the task. More importantly, these defects were associated with much lower gamma oscillations.

Since we wanted to know whether defects in gamma oscillations are responsible for memory impairments in AD conditions, we stimulated brain oscillations using optogenetics, and found that we could drastically improve memory performance when stimulating the gamma oscillations, but not any other frequency band. One of the most surprising findings was that such memory improvements could be observed in older mice that already started displaying plaques in brain regions associated with memory processing.

Our study suggests that memory impairments observed in Alzheimer’s disease are due to alterations of brain rhythms that occur long before any neuronal death and memory improvements can be observed even in the presence of amyloid plaques. While we are still years away from use of optogenetic techniques in humans, these results open the road for therapeutic strategies that are distinct to more classical antibody-based approaches and could help better understand AD pathology.

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