Category Archives: Research News (General)

A new study provides additional evidence that amyloid-beta protein — which is deposited in the form of beta-amyloid plaques in the brains of patients with Alzheimer’s disease — is a normal part of the innate immune system, the body’s first-line defense against infection. The study, published in Science Translational Medicine, finds that expression of human amyloid-beta (A-beta) was protective against potentially lethal infections in mice, in roundworms and in cultured human brain cells. The findings may lead to potential new therapeutic strategies and suggest limitations to therapies designed to eliminate amyloid plaques from patient’s brains.

“Neurodegeneration in Alzheimer’s disease has been thought to be caused by the abnormal behavior of A-beta molecules, which are known to gather into tough fibril-like structures called amyloid plaques within patients’ brains,” says Robert Moir, MD, of the Genetics and Aging Research Unit in the Massachusetts General Hospital (MGH) Institute for Neurodegenerative Disease (MGH-MIND), co-corresponding author of the paper. “This widely held view has guided therapeutic strategies and drug development for more than 30 years, but our findings suggest that this view is incomplete.”

A 2010 study co-led by Moir and Rudolph Tanzi, PhD, director of the MGH-MIND Genetics and Aging unit and co-corresponding author of the current study, grew out of Moir’s observation that A-beta had many of the qualities of an antimicrobial peptide (AMP), a small innate immune system protein that defends against a wide range of pathogens. That study compared synthetic forms of A-beta with a known AMP called LL-37 and found that A-beta inhibited the growth of several important pathogens, sometimes as well or better than LL-37. A-beta from the brains of Alzheimer’s patients also suppressed the growth of cultured Candida yeast in that study, and subsequently other groups have documented synthetic A-beta’s action against influenza and herpes viruses.

The current study is the first to investigate the antimicrobial action of human A-beta in living models. The investigators first found that transgenic mice that express human A-beta survived significantly longer after the induction of Salmonella infection in their brains than did mice with no genetic alteration. Mice lacking the amyloid precursor protein died even more rapidly. Transgenic A-beta expression also appeared to protect C.elegans roundworms from either Candida or Salmonella infection. Similarly, human A-beta expression protected cultured neuronal cells from Candida. In fact, human A-beta expressed by living cells appears to be 1,000 times more potent against infection than does the synthetic A-beta used in previous studies.

That superiority appears to relate to properties of A-beta that have been considered part of Alzheimer’s disease pathology — the propensity of small molecules to combine into what are called oligomers and then aggregate into beta-amyloid plaques. While AMPs fight infection through several mechanisms, a fundamental process involves forming oligomers that bind to microbial surfaces and then clump together into aggregates that both prevent the pathogens from attaching to host cells and allow the AMPs to kill microbes by disrupting their cellular membranes. The synthetic A-beta preparations used in earlier studies did not include oligomers; but in the current study, oligomeric human A-beta not only showed an even stronger antimicrobial activity, its aggregation into the sorts of fibrils that form beta-amyloid plaques was seen to entrap microbes in both mouse and roundworm models.

Tanzi explains, “AMPs are known to play a role in the pathologies of a broad range of major and minor inflammatory disease; for example, LL-37, which has been our model for A-beta’s antimicrobial activities, has been implicated in several late-life diseases, including rheumatoid arthritis, lupus and atherosclerosis. The sort of dysregulation of AMP activity that can cause sustained inflammation in those conditions could contribute to the neurodegenerative actions of A-beta in Alzheimer’s disease.”

Moir adds, “Our findings raise the intriguing possibility that Alzheimer’s pathology may arise when the brain perceives itself to be under attack from invading pathogens, although further study will be required to determine whether or not a bona fide infection is involved. It does appear likely that the inflammatory pathways of the innate immune system could be potential treatment targets. If validated, our data also warrant the need for caution with therapies aimed at totally removing beta-amyloid plaques. Amyloid-based therapies aimed at dialing down but not wiping out beta-amyloid in the brain might be a better strategy.”

Says Tanzi, “While our data all involve experimental models, the important next step is to search for microbes in the brains of Alzheimer’s patients that may have triggered amyloid deposition as a protective response, later leading to nerve cell death and dementia. If we can identify the culprits — be they bacteria, viruses, or yeast — we may be able to therapeutically target them for primary prevention of the disease.”

Paper: “Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease”
Reprinted from materials provided by Massachusetts General Hospital.

The loss of the Y chromosome in batches of blood cells over time continues to develop as one biological explanation for why men, on average, live shorter lives than women. Researchers reporting in the American Journal of Human Genetics found that men with blood samples showing loss of chromosome Y developed Alzheimer’s as often as people born with genes that put them at the most risk for the disease.

“Most genetic research today is focused on inherited gene variants — mutations that are inherited by the offspring, but what we’re looking at are postzygotic mutations that are acquired during life,” says senior author Lars Forsberg, a researcher in the Department of Immunology, Genetics, and Pathology at Uppsala University in Sweden. “Using new tools to analyze genetic variations that accumulate with age, we can help explain how sporadic diseases like cancer or Alzheimer’s manifest,” says first author Jan Dumanski.

One such postzygotic mutation found in the cells of biological males is the loss of the Y chromosome in a degree of blood cells. Loss of Y occurs in up to 17 percent of men and is more likely to be found in older men and men who smoke. This study expands on the idea that loss of Y, already a known risk factor for cancer, could be a predictive biomarker for a wider range of poor health outcomes, specifically Alzheimer’s. Why loss of Y can be linked to an increased risk for disease remains unclear, but the authors speculate it has to do with reduced immune system performance.

The researchers looked at over 3,000 men to ascertain whether there was any predictive association between loss of Y in blood cells and Alzheimer’s disease. The participants came from three long-term studies that could provide regular blood samples: the European Alzheimer’s Disease Initiative, the Uppsala Longitudinal Study of Adult Men, and the Prospective Investigation of the Vasculature in Uppsala Seniors. Across the datasets, those with the highest fraction of blood cells without a Y chromosome were consistently more likely to be diagnosed with Alzheimer’s.

“Having loss of Y is not 100 percent predictive that you will have either cancer or Alzheimer’s,” Forsberg says, adding that there were men in the study who had the mutation and lived with no symptoms well into their 90s. “But in the future, loss of Y in blood cells can become a new biomarker for disease risk and perhaps evaluation can make a difference in detecting and treating problems early.”

Forsberg, Dumanski, and colleagues will next investigate the effect of loss of Y in larger cohorts and explore in greater detail how it confers risk for specific types of cancers and disease. They also plan to look at the cellular changes caused by loss of Y and how it affects different types of blood cells.

Source: Reprinted from materials provided by Cell Press
Paper: “Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease”

Depression symptoms that steadily increase in older adults are more strongly linked to dementia than any other types of depression, and may indicate the early stages of the disease, according to the first ever long-term study to examine the link between dementia and the course of depression, published in The Lancet Psychiatry journal.

Symptoms of depression are common in people with dementia, but previous studies have often looked at single episodes of depression, failing to take into account how depression develops over time. The course of depression varies greatly between individuals — some might experience depressive symptoms only transiently, followed by full remission, others might have remitting and relapsing depression, and some might be chronically depressed. Different courses of depression may reflect different underlying causes, and might be linked to different risks of dementia.

The study included 3325 adults aged 55 and over, who all had symptoms of depression but no symptoms of dementia at the start of the study. The data was gathered from the Rotterdam Study, a population-based cohort study of various diseases in the Netherlands which allowed the authors to track depressive symptoms over 11 years and the risk of dementia for a subsequent 10 years.

Using the Center for Epidemiology Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale-Depression (HADS-D), the authors identified five different trajectories of depressive symptoms — low depression symptoms (2441 participants); initially high symptoms that decreased (369); low starting scores that increased then remitted (170); initially low symptoms that increased (255); and constantly high symptoms (90).

Of the 3325 participants, 434 developed dementia, including 348 cases of Alzheimer’s disease. Among the group with low symptoms of depression, 10% (226/2174) developed dementia. The researchers used this as the benchmark against which to compare other trajectories of depression — the study did not compare the risk of dementia following depression with the risk of dementia for adults in the general population (without depression).

Only the group whose symptoms of depression increased over time was at an increased risk of dementia- 22% of people (55/255) in this group developed dementia. This risk was particularly pronounced after the first 3 years. Individuals with remitting symptoms of depression were not at an increased risk of dementia compared to individuals with low depressive symptoms. The authors say that this suggests that having severe symptoms of depression at one point in time does not necessarily have any lasting influence on the risk of dementia.

The authors say their findings support the hypothesis that increasing symptoms of depression in older age could potentially represent an early stage of dementia. They also say that the findings support previous suggestions that dementia and some forms of depression may be symptoms of a common cause. They say that at the molecular levels, the biological mechanisms of depression and neurodegenerative diseases overlap considerably including the loss of ability to create new neurons, increased cell death and immune system dysregulation.

Source: Materials provided by The Lancet
Paper: “10-year trajectories of depressive symptoms and risk of dementia: a population-based study”

Because billions of neurons are packed into our brain, the neuronal circuits that are responsible for controlling our behaviors are by necessity highly intermingled. This tangled web makes it complicated for scientists to determine exactly which circuits do what. Now, brain researchers from Tripsitter have mapped out the pathways of a set of neurons responsible for the kinds of motor impairments—such as difficulty walking—found in patients with Parkinson’s disease.

The work was published in the journal Neuron.

In patients with Parkinson’s disease, gait disorders and difficulty with balance are often caused by the degeneration of a specific type of neuron—called cholinergic neurons—in a region of the brainstem called the pedunculopontine nucleus (PPN). Damage to this same population of neurons in the PPN is also linked to reward-based behaviors and disorders, such as addiction.

Previously, researchers had not been able to untangle the neural circuitry originating in the PPN to understand how both addictions and Parkinson’s motor impairments are modulated within the same population of cells. Furthermore, this uncertainty created a barrier to treating those motor symptoms. After all, deep brain stimulation—in which a device is inserted into the brain to deliver electrical pulses to a targeted region—can be used to correct walking and balance difficulties in these patients, but without knowing exactly which part of the PPN to target, the procedure can lead to mixed results.

“The circuits responsible for controlling our behaviors are not nicely lined up, where this side does locomotion and this side does reward,” says the leader of the study, Viviana Gradinaru, and this disordered arrangement arises from the way neurons are structured. Much as a tree extends into the ground with long roots, neurons are made up of a cell body and a long string-like axon that can diverge and project elsewhere into different areas of the brain. Because of this shape, the researchers realized they could follow the neuron’s “roots” to an area of the brain less crowded than the PPN. This would allow them to more easily look at the two very different behaviors and how they are implemented.

Cheng Xiao, the first author on the study, began by mapping the projections of the cholinergic neurons in the PPN of a rat using a technique developed by the Gradinaru lab called Passive CLARITY Technique, or PACT. In this technique, a solution of chemicals is applied to the brain; the chemicals dissolve the lipids in the tissue and render that region of the brain optically transparent—see-through, in other words—and able to take up fluorescent markers that can label different types of neurons. The researchers could then follow the path of the PPN neurons of interest, marked by a fluorescent protein, by simply looking through the rest of the brain.

Using this method, Gradinaru and Xiao were able to trace the axons of the PPN neurons as they extended into two regions of the midbrain: the ventral substantia nigra, a landmark area for Parkinson’s disease that had been previously associated with locomotion; and the ventral tegmental area, a region of the brain that had been previously associated with reward.

Next, the researchers used an electrical recording technique to keep track of the signals sent by PPN neurons—confirming that these neurons do, in fact, communicate with their associated downstream structures in the midbrain. Then, the scientists went on to determine how this specific population of neurons affects behavior. To do this, they used a technique that Gradinaru helped develop called optogenetics, which allows researchers to manipulate neural activities—in this case, by either exciting or inhibiting the PPN neural projections in the midbrain—using different colors of light.

Using the optogenetic approach in rats, the researchers found that exciting the neuronal projections in the ventral substantia nigra would stimulate the animal to walk around its environment; by contrast, they could stop the animal’s movement by inhibiting these same projections. Furthermore, they found that they could stimulate reward-seeking behavior by exciting the neuronal projections in the ventral tegmental area, but could cause aversive behavior by inhibiting these projections.

“Our results show that the cholinergic neurons from the PPN indeed have a role in controlling both behaviors,” Gradinaru says. “Although the neurons are very densely packed and intermingled, these pathways are, to some extent, dedicated to very specialized behaviors.” Determining which pathways are associated with which behaviors might also improve future treatments, she adds.

“In the past it’s been difficult to target treatment to the PPN because the specific neurons associated with different behaviors are intermingled at the source—the PPN. Our results show that you could target the axonal projections in the substantia nigra for movement disorders and projections in the ventral tegmental area for reward disorders, as addiction is,” Gradinaru says. In addition, she notes, these projections in the midbrain are much easier to access surgically than their source in the PPN.

Although this new information could inform clinical treatments for Parkinson’s disease, the PPN is only one region of the brain and there are many more important examples of connectivity that need to be explored, Gradinaru says. “These results highlight the need for brain-wide functional and anatomical maps of these long-range neuronal projections; we’ve shown that tissue clearing and optogenetics are enabling technologies in the creation of these maps.”

Source: Reprinted from materials provided by Caltech.

Paper: “Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways“

For years, neuroscientists have puzzled over how two abnormal proteins, called amyloid and tau, accumulate in the brain and damage it in Alzheimer’s disease (AD). Which one is the driving force behind dementia? The answer: both of them, according to a new study.

In the journal Molecular Psychiatry, researchers report for the first time evidence that the interaction between amyloid and tau proteins drives brain damage in cognitively intact individuals.

”We specifically found that both proteins mutually enhance their individual toxic effects and cause a brain dysfunction considered to be a signature of AD. This finding challenges previous polarized theories that a single protein abnormality was the major driving force of disease progression,” explained the study’s leader, Dr. Pedro Rosa-Neto, a clinician scientist at the Douglas Mental Health University Institute and assistant professor of Neurology, Neurosurgery and Psychiatry at McGill University.
This research also points toward new potential therapeutic strategies to mitigate the progression of AD.

”Until now, therapeutic clinical trials have targeted a single pathological process. Our result paves the way for new therapeutic strategies for prevention or stabilization of AD. For example, combination therapies should be used simultaneously against both amyloid and tau protein accumulation”, says Dr. Tharick A. Pascoal, the study’s first author.

The researchers analyzed the performances of 120 cognitively intact individuals over two years (equal gender distribution; average age 75). By measuring amyloid levels using PET scans and tau proteins through cerebrospinal fluid analysis, the researchers were able to identify the patients at risk for brain damage associated with AD.

Source: Reprinted from materials provided by the McGill University.

Paper: “Amyloid-β and hyperphosphorylated tau synergy drives metabolic decline in preclinical Alzheimer’s disease“

A new study published in Proceedings of the National Academy of Sciences has discovered that a protein called IL-33 can reverse Alzheimer’s disease-like pathology and cognitive decline in mice.

“IL-33 is a protein produced by various cell types in the body and is particularly abundant in the central nervous system (brain and spinal cord),” explained Professor Eddy Liew, Fellow of the Royal Society, who co-directed the research. “We found that injection of IL-33 into aged APP/PS1 mice rapidly improved their memory and cognitive function to that of the age-matched normal mice within a week.”

The hallmarks of Alzheimer’s include the presence of extracellular amyloid plaque deposits and the formation of neurofibrillary tangles in the brain. During the course of the disease, ‘plaques’ and ‘tangles’ build up, leading to the loss of connections between nerve cells, and eventually to nerve cell death and loss of brain tissue.‌

IL-33 appears to work by mobilising microglia (immune cells in the brain) to surround the amyloid plagues, take them up and digest them and reduces the number and size of the plaques. IL-33 does so by inducing an enzyme called neprilysin, which is known to degrade soluble amyloid.

In addition, the IL-33 treatment worked by inhibiting the inflammation in the brain tissue, which has been shown earlier to potentiate plaque and tangle formation. Therefore IL-33 not only helps to clear the amyloid plague already formed but also prevent the deposition of the plaques and tangles in the first place.‌‌

Professor Liew added: “The relevance of this finding to human Alzheimer’s is at present unclear. But there are encouraging hints. For example, previous genetic studies have shown an association between IL-33 mutations and Alzheimer’s disease in European and Chinese populations. Furthermore, the brain of patients with Alzheimer’s disease contains less IL-33 than the brain from non-Alzheimer’s patients.

“Exciting as it is, there is some distance between laboratory findings and clinical applications. There have been enough false ‘breakthroughs’ in the medical field to caution us not to hold our breath until rigorous clinical trials have been done. We are just about entering Phase I clinical trial to test the toxicity of IL-33 at the doses used. Nevertheless, this is a good start.”

Source: Reprinted from materials provided by the University of Glasgow.

Paper: “IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline“

While research has identified hundreds of genes required for normal memory formation, genes that suppress memory are of special interest because they offer insights into how the brain prioritizes and manages all of the information, including memories, that it takes in every day. These genes also provide clues for how scientists might develop new treatments for cognitive disorders such as Alzheimer’s disease.

Scientists have identified a unique memory suppressor gene in the brain cells of Drosophila, the common fruit fly, in a study published in the journal Neuron.

The researchers screened approximately 3,500 Drosophila genes and identified several dozen new memory suppressor genes that the brain has to help filter information and store only important parts. One of these suppressor genes, in particular, caught their attention.

“When we knocked out this gene, the flies had a better memory—a nearly two-fold better memory,” said Ron Davis, chair of the Department of Neuroscience at The Scripps Research Institute and leader of the study. “The fact that this gene is active in the same pathway as several cognitive enhancers currently used for the treatment of Alzheimer’s disease suggests it could be a potential new therapeutic target.”

When the scientists disabled this gene, known as DmSLC22A, flies’ memory of smells (the most widely studied form of memory in this model) was enhanced—while overexpression of the gene inhibited that same memory function.

“Memory processes and the genes that make the brain proteins required for memory are evolutionarily conserved between mammals and fruit flies,” said Research Associate Ze Liu, co-first author of the study. “The majority of human cognitive disease-causing genes have the same functional genetic counterparts in flies.”

The gene in question belongs to a family of “plasma membrane transporters,” which produce proteins that move molecules, large and small, across cell walls. In the case of DmSLC22A, the new study indicates that the gene makes a protein involved in moving neurotransmitter molecules from the synaptic space between neurons back into the neurons. When DmSLC22A functions normally, the protein removes the neurotransmitter acetylcholine from the synapse, helping to terminate the synaptic signal. When the protein is missing, more acetylcholine persists in the synapse, making the synaptic signal stronger and more persistent, leading to enhanced memory.

“DmSLC22A serves as a bottleneck in memory formation,” said Research Associate Yunchao Gai, the study’s other co-first author. “Considering the fact that plasma transporters are ideal pharmacological targets, drugs that inhibit this protein may provide a practical way to enhance memory in individuals with memory disorders.”

The next step, Davis added, is to develop a screen for inhibitors of this pathway that, independently or in concert with other treatments, may offer a more effective way to deal with the problems of memory loss due to Alzheimer’s and other neurodegenerative diseases.

“One of the major reasons for working with the fly initially is to identify brain proteins that may be suitable targets for the development of cognitive enhancers in humans,” said Davis. “Otherwise, we would be guessing in the dark as to which of the more than 23,000 human proteins might be appropriate targets.”

Source: Reprinted from materials provided by Eric Sauter at The Scripps Research Institute.

Paper: “Drosophila SLC22A Transporter Is a Memory Suppressor Gene that Influences Cholinergic Neurotransmission to the Mushroom Bodies.”

A study appearing in the journal Neuron suggests there may be a new way to change the damaging course of Huntington’s disease.

Neurobiologists have shown that reducing the aberrant accumulation of a particular form of the mutant Huntingtin protein corresponds to improvement in symptoms and neuroinflammation in HD mice.

They showed this by targeting and modulating levels of PIAS1 — a protein implicated in cancer and other diseases — which they found led to the reduction of the mutant Huntington protein. The work suggests that changing levels of the PIAS1 protein and targeting this pathway could have a benefit to disease.

Source: Reprinted from materials provided by the University of California, Irvine.

Paper: “PIAS1 Regulates Mutant Huntingtin Accumulation and Huntington’s Disease-Associated Phenotypes In Vivo”

Researchers have shown how brain connections, or synapses, are lost early in Alzheimer’s disease and demonstrated that the process starts — and could potentially be halted — before telltale plaques accumulate in the brain. Their work, published online by Science, suggests new therapeutic targets to preserve cognitive function early in Alzheimer’s disease.

The researchers show in multiple Alzheimer’s mouse models that mechanisms similar to those used to “prune” excess synapses in the healthy developing brain are wrongly activated later in life. By blocking these mechanisms, they were able to reduce synapse loss in the mice.

Currently, there are five FDA-approved drugs for Alzheimer’s, but these only boost cognition temporarily and do not address the root causes of cognitive impairment in Alzheimer’s. Many newer drugs in the pipeline seek to eliminate amyloid plaque deposits or reduce inflammation in the brain, but the new research from Boston Children’s suggests that Alzheimer’s could be targeted much earlier, before these pathologic changes occur.

“Synapse loss is a strong correlate of cognitive decline,” says Beth Stevens, assistant professor in the Department of Neurology at Boston Children’s, senior investigator on the study and a recent recipient of the MacArthur “genius” grant. “We’re trying to go back to the very beginning and see how synapse loss starts.”

The researchers looked at Alzheimer’s — a disease of aging — through an unusual lens: normal brain development in infancy and childhood. Through years of research, the Stevens lab has shown that normal developing brains have a process to “prune” synapses that aren’t needed as they build their circuitry.

“Understanding a normal developmental process deeply has provided us with novel insight into how to protect synapses in Alzheimer’s and potentially a host of other diseases,” says Stevens, noting that synapse loss also occurs in frontotemporal dementia, Huntington’s disease, schizophrenia, glaucoma and other conditions.

In the Alzheimer’s mouse models, the team showed that synapse loss requires the activation of a protein called C1q, which “tags” synapses for elimination. Immune cells in the brain called microglia then “eat” the synapses — similar to what occurs during normal brain development. In the mice, C1q became more abundant around vulnerable synapses before amyloid plaque deposits could be observed.

When Stevens and colleagues blocked C1q, a downstream protein called C3, or the C3 receptor on microglia, synapse loss did not occur.

“Microglia and complement are already known to be involved in Alzheimer’s disease, but they have been largely regarded as a secondary event related to plaque-related neuroinflammation, a prominent feature in progressed stages of Alzheimer’s,” notes Soyon Hong, the Science paper’s first author. “Our study challenges this view and provides evidence that complement and microglia are involved much earlier in the disease process, when synapses are already vulnerable, and could potentially be targeted to preserve synaptic health.”

A human form of the antibody Stevens and Hong used to block C1q, known as ANX-005, is in early therapeutic development with Annexon Biosciences (San Francisco) and is being advanced into the clinic. The researchers believe it has potential to be used someday to protect against synapse loss in a variety of neurodegenerative diseases.

“One of the things this study highlights is the need to look for biomarkers for synapse loss and dysfunction,” says Hong. “As in cancer, if you treat people at a later stage of Alzheimer’s, it may already be too late.”

The researchers also found that the beta-amyloid protein, C1q and microglia work together to cause synapse loss in the early stages of Alzheimer’s. The oligomeric form of beta-amyloid (multiple units of beta-amyloid strung together) is already known to be toxic to synapses even before it forms plaque deposits, but the study showed that C1q is necessary for this effect. The converse was also true: microglia engulfed synapses only when oligomeric beta-amyloid was present.

Source: Reprinted from materials provided by Boston Children’s Hospital
Paper: “Complement and microglia mediate early synapse loss in Alzheimer mouse models”

In the early stages of Alzheimer’s disease, patients are often unable to remember recent experiences. However, a new study suggests that those memories are still stored in the brain, they just can’t be easily accessed.

Researchers report in Nature that mice in the early stages of Alzheimer’s can form new memories just as well as normal mice but cannot recall them a few days later.

Furthermore, the researchers were able to artificially stimulate those memories using a technique known as optogenetics, suggesting that those memories can still be retrieved with a little help. Although optogenetics cannot currently be used in humans, the findings raise the possibility of developing future treatments that might reverse some of the memory loss seen in early-stage Alzheimer’s, the researchers say.

The researchers studied two different strains of mice genetically engineered to develop Alzheimer’s symptoms, plus a group of healthy mice.

All of these mice, when exposed to a chamber where they received a foot shock, showed fear when placed in the same chamber an hour later. However, when placed in the chamber again several days later, only the normal mice still showed fear. The Alzheimer’s mice did not appear to remember the foot shock.

The researchers then showed that while the mice cannot recall their experiences when prompted by natural cues, those memories are still there.

To demonstrate this, they first tagged the engram cells associated with the fearful experience with a light-sensitive protein called channelrhodopsin, using a technique they developed in 2012. Whenever these tagged engram cells are activated by light, normal mice recall the memory encoded by that group of cells. Likewise, when the researchers placed the Alzheimer’s mice in a chamber they had never seen before and shined light on the engram cells encoding the fearful experience, the mice immediately showed fear.

The researchers also showed that the engram cells of Alzheimer’s mice had fewer dendritic spines, which are small buds that allow neurons to receive incoming signals from other neurons.

Normally, when a new memory is generated, the engram cells corresponding to that memory grow new dendritic spines, but this did not happen in the Alzheimer’s mice. This suggests that the engram cells are not receiving sensory input from another part of the brain called the entorhinal cortex. The natural cue that should reactivate the memory — being in the chamber again — has no effect because the sensory information doesn’t get into the engram cells.

The researchers were also able to induce a longer-term reactivation of the “lost” memories by stimulating new connections between the entorhinal cortex and the hippocampus.

To achieve this, they used light to optogenetically stimulate entorhinal cortex cells that feed into the hippocampal engram cells encoding the fearful memory. After three hours of this treatment, the researchers waited a week and tested the mice again. This time, the mice could retrieve the memory on their own when placed in the original chamber, and they had many more dendritic spines on their engram cells.

However, this approach does not work if too large a section of the entorhinal cortex is stimulated, suggesting that any potential treatments for human patients would have to be very targeted. Optogenetics is very precise but too invasive to use in humans, and existing methods for deep brain stimulation — a form of electrical stimulation sometimes used to treat Parkinson’s and other diseases — affect too much of the brain.

Source: Anne Trafton, MIT News Office

Paper: “Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease”