Evidence Suggests that, at Least in Earlier Stages, Alzheimer's Disease Blocks Rather than Destroys Memories

For years now, evidence has accumulated to suggest that Alzheimer's disease blocks memory retrieval rather than destroying memories, at least in the earlier stages prior to the onset of widespread destruction of neurons. Today's research is more of the same. This and related results raise the hope that success in any of the mainstream efforts to treat the causes of this disease should restore much of the cognitive function lost to the condition. Of course it is worth recalling that Alzheimer's patients rarely suffer Alzheimer's alone: it usually arrives alongside one or more other forms of neurodegeneration, each with distinct mechanisms that cause neurons to malfunction or be destroyed. This is in part because Alzheimer's disease is to some degree a lifestyle condition; not as greatly as is the case for type 2 diabetes, but being sedentary and overweight greatly raises the risk of both Alzheimer's and, separately, sufficiently accelerated vascular aging to cause vascular dementia or other forms of neurodegenerative condition. The brain has sizable energy demands, and is particularly vulnerable to the slow age-related failure in delivery of oxygen and nutrients.

It is worth noting that a lot of mouse breeding goes on behind the scenes in the sort of research noted here, very reliant as it is on genetic engineering. This work involved crossing three lineages. Many of the tools to investigate biochemistry in living beings take the form of genetic machinery that can be activated to tag specific cells or visualize a specific protein interaction. Each such tool is made manifest as a lineage of genetically altered mice; the change must be created early in or prior to embryonic development, as the research community still lacks a standardized toolkit for applying genetic changes to adults. If a research group wants to use multiple tools in a single experiment, then mice of the relevant lineages must be mated to obtain a cross-bred lineage. The same is true when applying a tool to a mouse model of a specific disease. Again, more cross-breeding. This is expensive and time-consuming. It is also one of the many things that will be replaced in the near future with some form of effective gene therapy platform - probably related to CRISPR - that can be deployed in adult mice, thus reducing costs and speeding progress. This is the point of the Maximally Modifiable Mice developed by the SENS Research Foundation, a program that aims to create mice equipped with a set of genetic machinery that can accept arbitrary updates in a sort of plug-and-play fashion.

Lasers reactivate 'lost' memories in mice with Alzheimer's

It has long been assumed that Alzheimer's disease completely erases memories. The condition involves clumps of proteins known as amyloid plaques and tau tangles accumulating in the brain, where they are thought to destroy the neurons that store our memories. But experiments suggest that memories may not be wiped by Alzheimer's disease, but instead become harder to access. What's more, these memories can be reawakened by artificially activating the neurons they are stored in.

To examine how memory is affected by Alzheimer's disease, the researchers developed a way of visualising individual memories in mouse brains. They genetically engineered mice with neurons that glow yellow when activated during memory storage, and red when activated during memory recall. Two sets of these mice were created - one set that was healthy, and one with a condition resembling human Alzheimer's disease. Both sets of mice took a memory test. First, they were exposed to a lemon scent and given an electric shock. Then, a week later, they were exposed to the same lemon scent. The healthy mice immediately froze in anticipation of being shocked again. But the mice with Alzheimer's disease froze almost half as much as the healthy mice, suggesting they did not remember the link between the smell and shock so strongly.

This behaviour matched what the team saw in the hippocampi of the mice - the brain regions that record memories. In healthy mice, the red and yellow neurons overlapped, showing that the mice were retrieving the lemon-shock memory from the same place it had been stored. But in the Alzheimer's mice, different cells glowed red during recall, suggesting that they were calling up the wrong memories. This might help explain why people with Alzheimer's disease commonly experience false memories.

Using a genetic engineering technique called optogenetics, the team went on to reactivate the lemon-shock memory in the Alzheimer's mice. By shining a blue laser down a fibre optic cable into the brain, they were able to stimulate the yellow memory-storing neurons, prompting the mice to freeze when they smelled the lemon scent. This shows that "lost" memories may still exist in the brain, and can be recovered. Optogenetics is not a technique that can be used in people yet, because it isn't yet safe or practical to tinker with our neurons or stick lasers in our brains. But in the future, targeted drugs or techniques like deep-brain stimulation may help people with Alzheimer's access their forgotten memories. The next step will be to confirm that the same memory storage and retrieval mechanisms exist in people with Alzheimer's disease, because mouse models do not perfectly reflect the condition in humans. In particular, the number of neurons that die in mouse models of Alzheimer's disease is far lower than in humans.

Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. APPswe/PS1dE9 (APP/PS1) mice have been developed as an AD model and are characterized by plaque formation at 4-6 months of age. Here, we sought to better understand AD-related cognitive decline by characterizing various types of memory. In order to better understand how memory declines with AD, APP/PS1 mice were bred with ArcCreERT2 mice. In this line, neural ensembles activated during memory encoding can be indelibly tagged and directly compared with neural ensembles activated during memory retrieval (i.e., memory traces/engrams).

We first administered a battery of tests examining depressive- and anxiety-like behaviors, as well as spatial, social, and cognitive memory to APP/PS1 × ArcCreERT2 × channelrhodopsin (ChR2)-enhanced yellow fluorescent protein (EYFP) mice. Dentate gyrus (DG) neural ensembles were then optogenetically stimulated in these mice to improve memory impairment. AD mice had the most extensive differences in fear memory, as assessed by contextual fear conditioning (CFC), which was accompanied by impaired DG memory traces. Optogenetic stimulation of DG neural ensembles representing a CFC memory increased memory retrieval in the appropriate context in AD mice when compared with control mice. Moreover, optogenetic stimulation facilitated reactivation of the neural ensembles that were previously activated during memory encoding. These data suggest that activating previously learned DG memory traces can rescue cognitive impairments and point to DG manipulation as a potential target to treat memory loss commonly seen in AD.

Comments

This makes an argument for cryonics and that cryonics should be legal before clinical death. It should be legal to cryopreserve your body in early AD stage.

Posted by: Norse at July 29th, 2017 4:24 AM

Imagine by 2035 it's possible to create a backup image of your brain using modern MRI technology. They're currently lacking a factor of 10 in resolution, but there's no hard limit to MRI resolution, so it's really just a question of time until they get there.

http://www.bbc.com/news/health-40488545
(What the brain's wiring looks like)

Furthermore it's possible to simulate the brain in a computer. The software is ready, the hardware will be soon.

https://www.humanbrainproject.eu/en/

Now what would you like to be? The image made in early AD or in late AD?

Imagine a cryonics company does that to "reanimate" you. Would you like that or should they delete you?

Posted by: Matthias F at July 29th, 2017 8:17 AM

Now completely unrelated to Alzehimers or aging in general, I was thinking how important it will be to effectively treat depression. When I see how many people kill themselves because of it and it would suffice to have a severe depression once in a potential very long lifespan, I think this should not be underestimated. Sorry for derailing, but was just a consideration that crossed my mind this moment.

Posted by: K. at July 29th, 2017 8:36 AM

Suicide is the number one non-natural cause of death in Spain.

Posted by: Antonio at July 29th, 2017 10:26 AM

@Mathias
If the aim is to make an emulation of me, even you put reanimate in quotation marks there so you're aware that's not a real person anymore (let alone the person it's supposed to be), then my answer is - neither.
This is why I'm not and have absolutely no plans of using a cryonics plan.

If you want a copy of you to be made, just make a vlog and write a diary. It's probably going to create a better version of you anyway because we filter the less agreeable parts of our personality when we produce memories.
It's cheaper too - virtually free.

Emulation cultists have absolutely no reason to safe any physical part of themselves if I have to be honest. Waste of time and resources and it creates unneeded friction with your family.

Posted by: Anonymoose at July 29th, 2017 11:27 AM

@Anonymoose

Cryonics doesn't imply mind uploading.

Posted by: Antonio at July 29th, 2017 12:54 PM

You don't know what it implies.
You'd be dead and as far as I know none of the documents you sign ensures you'd be revived one way or another. And even if you did sign such a document there is no legal framework to ensure it is enforced.

It is a very disturbing grey area, but not the only problem I personally find in cryonics. You are of course free to sign up yourself, I'm not condemning anyone who finds peace in the procedure.

Posted by: Anonymoose at July 29th, 2017 1:19 PM

@Anonymoose
That's an interesting thought. If such a ghost image doesn't count as a real person (I think that will legally be the case) then it better be a nice person so they keep it around as a reminder. Someone may even leave it as a legacy for his relatives. If virtual grandpa is nice he can play with the kids or the family may ask him for advice. If he gets a job in cyberspace - good for everybody.

I don't think it would be very expensive. A MRI scan costs somewhere around $600 and computer hardware will be cheap as dirt in the future.

Posted by: Matthias F at July 29th, 2017 1:58 PM

You really don't get what I'm saying. Alcor can say whatever they want because they are not held accountable by anyone.
There is simply no legal structure that enforces their compliance.

Posted by: Anonymoose at July 29th, 2017 3:10 PM

They are not accounted only by the law.

Posted by: Antonio at July 29th, 2017 3:21 PM

@Anonymoose:
Trust me: Cryonicists are idealists, working hard to improve all aspects of cryonics from standby to future revival to make its success more and more realistic. They neither do it for fun nor is money the main driver (That's why almost all cryonics organizations are non-profit). Although it would be nice to have laws in place regarding cryonics, they're not absolutely necessary IMO.

Posted by: Nicolai at July 31st, 2017 2:32 AM

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.