Thursday 31 March 2016

Bringing Back Memories to Alzheimer’s Patients

by Sara Adaes, PhD

 Memory loss is one of the most well-known and heartbreaking consequences of Alzheimer’s disease. As Alzheimer’s starts to develop, episodic memory starts to decline. This means that the memory of personal experiences and events, and of the time, place and emotional context of those experiences starts to fade.
Memory requires the ability to encode, consolidate, store and retrieve information. Whenever one of these processes is compromised, memories are inaccessible, either because they were never encoded or stored in the first place, or because, even though they’re in there somewhere, we’re unable to access them.
What has been unclear, in Alzheimer’s patients, is what part of memory is disrupted. Since recent experiences are the first to be forgotten, the ability to store new information has been regarded as the most compromised aspect of memory mechanisms in Alzheimer’s patients, at least in early stages. Some studies have supported this hypothesis, but this is not an easy thing to determine beyond doubt with the tools we currently have. How can we be sure if a memory was not stored, or if it is just inaccessible? It’s not easy to bypass the process of memory recall to check if a memory is stored.
Studies in animals have provided invaluable insights into the neurological mechanisms of memory impairment in Alzheimer’s disease. A new study recently published in Nature sheds more light into the mechanisms of memory impairment associated with Alzheimer’s. Most importantly, this study brings new hope to the possibility of recovering lost memories.
Are memories absent, or just unreachable?
Using a mouse model of Alzheimer’s disease, a group of researchers from the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory set out to determine whether or not memories are still stored but just inaccessible.
The researchers designed a very simple yet enlightening experiment: two groups of mice genetically engineered to develop Alzheimer’s symptoms, one with early stage Alzheimer’s and another with an advanced version of the disease, along with a group of healthy mice, were placed in a chamber where they received a shock to the foot.
When placed in the same chamber an hour after the initial foot shock, both healthy and early-stage Alzheimer’s mice showed fear, whereas advanced-stage Alzheimer’s mice did not. This demonstrated that, unlike advanced-stage Alzheimer’s mice, those with early-stage symptoms could still encode and store memories on a short-term time frame.
However, when the animals were placed in the same chamber 24 hours after the initial shock, only the healthy mice showed signs of fear. Mice with Alzheimer’s symptoms did not appear to remember the foot shock, suggesting that, although that new memory had been stored, these mice were now unable to retrieve it. It’s as if they couldn’t find it anymore.

Bringing memories back to light

The researchers then studied the possibility of recovering those memories in mice with early-stage Alzheimer’s. First off, they used molecular, genetic and optogenetic methods to identify the neuronal cells which hold traces (engrams) of that fearful memory of the foot shock, and tagged them with a light-sensitive molecule. Then, using blue light, they stimulated those specific cells in the hippocampus that drive memory recall, the memory engram cells. This method had already been shown to allow the retrieval of lost memories in other contexts of memory loss.
The authors showed that blue-light stimulation could indeed bring back the memory of the foot shock. The direct activation of the cells that were holding the memory allowed them to retrieve it as effectively as in healthy rats.
This study also showed that these memory-holding neurons have structural changes that affect their communication with other cells. These changes impair their ability to receive sensory information from other cells, which would act as a cue for memory recall. In other words, the memory is stored, but when the mice is placed in that chamber were the foot shock happened, the sight of the chamber does not trigger the fearful memory as it otherwise would. The blue-light stimulation acts as a replacement for that sensory trigger of memory.
From this study, we can infer that new memories may also still be formed in the early stages of Alzheimer’s disease in humans, but that their retrieval may be compromised. Importantly, this memory loss may be overcome using brain stimulation. Although this technology is still far from being applicable to humans, this study brings new optimism to Alzheimer’s disease therapy.

Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, & Tonegawa S (2012). Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature, 484 (7394), 381-5 PMID: 22441246
Roy DS, Arons A, Mitchell TI, Pignatelli M, Ryan TJ, & Tonegawa S (2016). Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature, 531 (7595), 508-12 PMID: 26982728
Ryan TJ, Roy DS, Pignatelli M, Arons A, & Tonegawa S (2015). Memory. Engram cells retain memory under retrograde amnesia. Science (New York, N.Y.), 348 (6238), 1007-13 PMID: 26023136
Tonegawa S, Liu X, Ramirez S, & Redondo R (2015). Memory Engram Cells Have Come of Age. Neuron, 87 (5), 918-31 PMID: 26335640
Tonegawa S, Pignatelli M, Roy DS, & Ryan TJ (2015). Memory engram storage and retrieval. Current opinion in neurobiology, 35, 101-9 PMID: 26280931

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