memory loss

A new culprit in cognitive decline in Alzheimer's disease

Study finds blood protein destroys memory storage sites in the brain and may lead to new treatments

February 5, 2019

Science Daily/Gladstone Institutes

Scientists have shown for the first time that a blood-clotting protein called fibrinogen is responsible for a series of molecular and cellular events that can destroy connections between neurons in the brain and result in cognitive decline.

 

It has long been known that patients with Alzheimer's disease have abnormalities in the vast network of blood vessels in the brain. Some of these alterations may also contribute to age-related cognitive decline in people without dementia. However, the ways in which such vascular pathologies contribute to cognitive dysfunction have largely remained a mystery. Until now, that is.

 

Scientists at the Gladstone Institutes, led by Senior Investigator Katerina Akassoglou, PhD, showed for the first time that a blood-clotting protein called fibrinogen is responsible for a series of molecular and cellular events that can destroy connections between neurons in the brain and result in cognitive decline.

 

Akassoglou and her team used state-of-the-art imaging technology to study both mouse brains and human brains from patients with Alzheimer's disease. They also produced the first three-dimensional volume imaging showing that blood-brain barrier leaks occur in Alzheimer's disease.

 

In their study, published in the scientific journal Neuron, the researchers found that fibrinogen, after leaking from the blood into the brain, activates the brain's immune cells and triggers them to destroy important connections between neurons. These connections, called synapses, are critical for neurons to communicate with one another.

 

Previous studies have shown that elimination of synapses causes memory loss, a common feature in Alzheimer's disease and other dementias. Indeed, the scientists showed that preventing fibrinogen from activating the brain's immune cells protected mouse models of Alzheimer's disease from memory loss.

 

"We found that blood leaks in the brain can cause elimination of neuronal connections that are important for memory functions," explains Akassoglou, who is also a professor of neurology at UC San Francisco (UCSF). "This could change the way we think about the cause and possible cure of cognitive decline in Alzheimer's disease and other neurological diseases."

 

The team showed that fibrinogen can have this effect even in brains that lack amyloid plaques, which are the focus of diverse treatment strategies that have failed in large clinical trials. The researchers showed that injecting even extremely small quantities of fibrinogen into a healthy brain caused the same kind of immune cell activation and loss of synapses they saw in Alzheimer's disease.

 

"Traditionally, the build-up of amyloid plaques in the brain has been seen as the root of memory loss and cognitive decline in Alzheimer's disease," says Mario Merlini, first author of the study and a staff research scientist in Akassoglou's laboratory at Gladstone. "Our work identifies an alternative culprit that could be responsible for the destruction of synapses."

 

The scientists' data help explain findings from recent human studies in which elderly people with vascular pathology showed similar rates of cognitive decline as age-matched people with amyloid pathology. However, patients with both types of pathology had much worse and more rapid cognitive decline. Other studies also identified vascular pathology as a strong predictor of cognitive decline that can act independently of amyloid pathology.

 

"Given the human data showing that vascular changes are early and additive to amyloid, a conclusion from those studies is that vascular changes may have to be targeted with separate therapies if we want to ensure maximum protection against the destruction of neuronal connections that leads to cognitive decline," says Akassoglou.

 

Interestingly, Akassoglou and her colleagues recently developed an antibody that blocks the interaction between fibrinogen and a molecule on the brain's immune cells. In a previous study, they showed this antibody protected mouse models of Alzheimer's disease from brain inflammation and neuronal damage.

 

"These exciting findings greatly advance our understanding of the contributions that vascular pathology and brain inflammation make to the progression of Alzheimer's disease," said Lennart Mucke, MD, co-author of the study and director of the Gladstone Institute of Neurological Disease. "The mechanisms our study identified may also be at work in a range of other diseases that combine leaks in the blood-brain barrier with neurological decline, including multiple sclerosis, traumatic brain injury, and chronic traumatic encephalopathy. It has far-reaching therapeutic implications."

https://www.sciencedaily.com/releases/2019/02/190205115419.htm

Canola oil linked to worsened memory and learning ability in Alzheimer's

December 7, 2017

Science Daily/Temple University Health System

Canola oil is one of the most widely consumed vegetable oils, yet little is known about its health effects. Now, a study links canola oil consumption in the diet with worsened memory, worsened learning ability and weight gain in mice which model Alzheimer's disease. It's the first study to suggest that canola oil is more harmful than healthful for the brain.

 

"Canola oil is appealing because it is less expensive than other vegetable oils, and it is advertised as being healthy," explained Domenico Praticò, MD, Professor in the Departments of Pharmacology and Microbiology and Director of the Alzheimer's Center at LKSOM, as well as senior investigator on the study. "Very few studies, however, have examined that claim, especially in terms of the brain."

 

Curious about how canola oil affects brain function, Dr. Praticò and Elisabetta Lauretti, a graduate student in Dr. Pratico's laboratory at LKSOM and co-author on the new study, focused their work on memory impairment and the formation of amyloid plaques and neurofibrillary tangles in an Alzheimer's disease mouse model. Amyloid plaques and phosphorylated tau, which is responsible for the formation of tau neurofibrillary tangles, contribute to neuronal dysfunction and degeneration and memory loss in Alzheimer's disease. The animal model was designed to recapitulate Alzheimer's in humans, progressing from an asymptomatic phase in early life to full-blown disease in aged animals.

 

Dr. Praticò and Lauretti had previously used the same mouse model in an investigation of olive oil, the results of which were published earlier in 2017. In that study, they found that Alzheimer mice fed a diet enriched with extra-virgin olive oil had reduced levels of amyloid plaques and phosphorylated tau and experienced memory improvement. For their latest work, they wanted to determine whether canola oil is similarly beneficial for the brain.

 

The researchers started by dividing the mice into two groups at six months of age, before the animals developed signs of Alzheimer's disease. One group was fed a normal diet, while the other was fed a diet supplemented with the equivalent of about two tablespoons of canola oil daily.

 

The researchers then assessed the animals at 12 months. One of the first differences observed was in body weight -- animals on the canola oil-enriched diet weighed significantly more than mice on the regular diet. Maze tests to assess working memory, short-term memory, and learning ability uncovered additional differences. Most significantly, mice that had consumed canola oil over a period of six months suffered impairments in working memory.

 

Examination of brain tissue from the two groups of mice revealed that canola oil-treated animals had greatly reduced levels of amyloid beta 1-40. Amyloid beta 1-40 is the more soluble form of the amyloid beta proteins. It generally is considered to serve a beneficial role in the brain and acts as a buffer for the more harmful insoluble form, amyloid beta 1-42.

 

As a result of decreased amyloid beta 1-40, animals on the canola oil diet further showed increased formation of amyloid plaques in the brain, with neurons engulfed in amyloid beta 1-42. The damage was accompanied by a significant decrease in the number of contacts between neurons, indicative of extensive synapse injury. Synapses, the areas where neurons come into contact with one another, play a central role in memory formation and retrieval.

 

"Amyloid beta 1-40 neutralizes the actions of amyloid 1-42, which means that a decrease in 1-40, like the one observed in our study, leaves 1-42 unchecked," Dr. Praticò explained. "In our model, this change in ratio resulted in considerable neuronal damage, decreased neural contacts, and memory impairment."

 

The findings suggest that long-term consumption of canola oil is not beneficial to brain health. "Even though canola oil is a vegetable oil, we need to be careful before we say that it is healthy," Dr. Praticò said. "Based on the evidence from this study, canola oil should not be thought of as being equivalent to oils with proven health benefits."

 

The next step is to carry out a study of shorter duration to determine the minimum extent of exposure necessary to produce observable changes in the ratio of amyloid beta 1-42 to 1-40 in the brain and alter synapse connections. A longer study may be warranted in order to determine whether canola oil also eventually impacts tau phosphorylation, since no effects on tau were observed over the six-month exposure period.

 

"We also want to know whether the negative effects of canola oil are specific for Alzheimer's disease," Dr. Praticò added. "There is a chance that the consumption of canola oil could also affect the onset and course of other neurodegenerative diseases or other forms of dementia."

https://www.sciencedaily.com/releases/2017/12/171207141624.htm

To forget or to remember? Memory depends on subtle brain signals

November 22, 2017

Science Daily/Scripps Research Institute

Understanding how brains actively erase memories may open new understanding of memory loss and aging, and open the possibility of new treatments for neurodegenerative disease.

 

The fragrance of hot pumpkin pie can bring back pleasant memories of holidays past, while the scent of an antiseptic hospital room may cause a shudder. The power of odors to activate memories both pleasing and aversive exists in many animals, from humans to the humble fruit fly.

 

Scientists on the Florida campus of The Scripps Research Institute (TSRI), writing in the journal Cell Reports, detailed how the intricate biochemical mechanism for storing scent-associated memories differs slightly from a less-understood mechanism for erasing unnecessary memories.

 

Understanding how brains actively erase memories may open new understanding of memory loss and aging, and open the possibility of new treatments for neurodegenerative disease.

 

In multiple ways, the processes of forgetting and remembering are alike. In fruit fly models of odor-associated learning, both the saving and erasure of memories involves dopamine activation of the brain cells. This clue in flies is important for understanding the human brain.

 

"The olfactory systems of flies and humans are actually quite similar in terms of neuron types and their connections," said study leader Ron Davis, Ph.D., co-chair of TSRI's Neuroscience Department.

 

Also, in both cases, activation of the neurons causes them to make an identical messenger molecule, cyclic AMP, leading to a cascade of activity within the cell, either building or breaking down memory storage, added Davis.

 

"So how do the cells know when they are getting a forgetting signal verses an acquisition signal? That was the huge, perplexing question," Davis said.

 

TSRI Professor Kirill Martemyanov, Ph.D., and Staff Scientist Ikuo Masuho, Ph.D., found that a type of signaling protein in neurons played a role. Masuho and Martemyanov screened a panel of these signaling proteins, called G proteins, against cells that expressed two key receptors known to be involved in memory and forgetting.

 

The TSRI team found one G protein, called G alpha S, that latched on to a neural dopamine receptor called dDA1, associated with memory formation. They found a different G protein, called G alpha Q, linked up with a nearby dopamine receptor called Damb, associated with the machinery of forgetting.

 

The next question was whether those two different G proteins could be controllers of the fly brain's memory machinery. To find out, the researchers silenced genes involved in the production of the G alpha Q protein in the flies. The flies with the protein silenced were exposed to odors in aversive situations and sent through mazes to see how well they remembered to turn away in the presence of the scent.

 

"If you removed G alpha Q, the flies should not forget, and indeed, they did not," Davis said. "They remembered better."

 

It appears in flies that some level of forgetting is a constant, healthy process, he said.

 

"The idea is, constantly as we learn information, there is a slow process that whittles away memories, and it continues whittling them away unless another part of the brain signals the memory is important and overrides it," Davis said.

 

It may be that the process of acquiring and forgetting memories ebbs and flows in a state of balance, he said. Important memories like the taste of mom's pumpkin pie might be forever retained, but trivialities like what you wore 10 years ago can fade into oblivion without consequence.

 

"If you have too much memory that is old and unnecessary, why keep them around? Why shouldn't you have a system for removing those for optimal function of the brain?" Davis asked. "We're getting all this information, all this learning during the day, and the brain may be saying, 'No, no, bring me back to my basal, my happy state.'"

 

Many questions remain to be solved, Davis noted. "We need to figure out what is downstream -- walk down the pathway to find the complete signaling system for forgetting," he said. "We are very early in this research."

https://www.sciencedaily.com/releases/2017/11/171122093120.htm

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