NPTX2

Scientists have developed an innovative neural cell culture model, shedding light on the intricate mechanisms underlying neurodegeneration. Their research pinpointed a misbehaving protein as a promising therapeutic target in the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Scientists at the University of Zurich have developed an innovative neural cell culture model, shedding light on the intricate mechanisms underlying neurodegeneration. Their research pinpointed a misbehaving protein as a promising therapeutic target in the treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neurodegenerative diseases cause some of the neurons in our brains to die, resulting in different symptoms depending on the brain region affected. In amyotrophic lateral sclerosis (ALS), neurons in the motor cortex and spinal cord degenerate, leading to paralysis. In frontotemporal dementia (FTD), on the other hand, neurons located in the parts of the brain involved in cognition, language and personality are affected. Both ALS and FTD are relentlessly progressive diseases and effective treatments are still lacking. As the population ages, the prevalence of age-related neurodegenerative diseases such as ALS and FTD is expected to increase. Despite the identification of the aberrant accumulation of a protein called TDP-43 in neurons in the central nervous system as a common factor in the vast majority of ALS and about half of FTD patients, the underlying cellular mechanisms driving neurodegeneration remain largely unknown. Flexible, durable, reproducible: ideal cell culture model for ALS and FTD research In their study, first author Marian Hruska-Plochan and corresponding author Magdalini Polymenidou of the Department of Quantitative Biomedicine at the University of Zurich developed a novel neural cell culture model that replicates the aberrant behavior of TDP-43 in neurons. Using this model, they discovered a toxic increase in the protein NPTX2, suggesting it as a potential therapeutic target for ALS and FTD. To mimic neurodegeneration, Marian Hruska-Plochan developed a new cell culture model called "iNets," derived from human induced pluripotent stem cells. These cells, originated from skin cells and reprogrammed to a very early, undifferentiated stage in the laboratory, serve as a source for developing many different, desired cell types. iNets are a network of interconnected neurons and their supporting cells growing in multiple layers in a dish. The cultures lasted exceptionally long -- up to a year -- and were easily reproduced. "The robustness of aging iNets allows us to perform experiments that would not have been possible otherwise," says Hruska-Plochan. "And the flexibility of the model makes it suitable for a wide range of experimental methodologies." As a case in point, the iNets cell cultures provided the ideal model to investigate the progression from TDP-43 dysfunction to neurodegeneration. How protein dysfunction leads to neurodegeneration Employing the iNets model, the researchers identified a toxic accumulation of NPTX2, a protein normally secreted by neurons through synapses, as the missing link between TDP-43 misbehavior and neuronal death. To validate their hypothesis, they examined brain tissue from deceased ALS and FTD patients and indeed found that, also in patients, NPTX2 accumulated in cells containing abnormal TDP-43. This means that the iNets culture model accurately predicted ALS and FTD patient pathology. In additional experiments in the iNets model, the researchers tested whether NPTX2 could be a target for drug design to treat ALS and FTD. The team engineered a setup in which they lowered the levels of NPTX2 while neurons were suffering from TDP-43 misbehavior. They found that keeping NPTX2 levels low counteracted neurodegeneration in the iNets neurons. Therefore, drugs that reduce the amount of the protein NPTX2 have potential as a therapeutic strategy to halt neurodegeneration in ALS and FTD patients. Magdalini Polymenidou sees great promise in this discovery: "We still have a long way to go before we can bring this to the patients, but the discovery of NPTX2 gives us a clear shot of developing a therapeutic that acts at the core of the disease," she said. "In conjunction with two additional targets recently identified by other research teams, it is conceivable that anti-NPTX2 agents could emerge as a key component of combination therapies for ALS and FTD in the future," she added.

Results of a long-term, federally funded study of cognitively healthy adults -- most with a family history of Alzheimer's disease -- have added to evidence that low spinal fluid levels of a protein linked to learning and memory in mice may serve as an early predictor of mild cognitive impairment (MCI) years before symptoms appear. Results of a long-term, federally funded study of cognitively healthy adults -- most with a family history of Alzheimer's disease -- have added to evidence that low spinal fluid levels of a protein linked to learning and memory in mice may serve as an early predictor of mild cognitive impairment (MCI) years before symptoms appear. The findings, which may potentially offer new targets for treating or preventing Alzheimer's and other dementias, showed that a relatively low level of the protein known as NPTX2 is not only a likely standalone risk factor for MCI and Alzheimer's dementia, but also improves prediction of cognitive impairment after accounting for levels of traditional biomarkers and well-established genetic risk factors for Alzheimer's. The study, conducted by Johns Hopkins Medicine scientists on more than 250 primarily middle-aged adults, the vast majority of whom were white, concluded that the findings were consistent with and expand prior studies by establishing that measurements of NPTX2 in cerebrospinal fluid were predictive of MCI onset within or even beyond seven years before symptoms occurred. A report on the study was published July 25 in the Annals of Neurology. According to the Alzheimer's Association, MCI, marked by mild memory loss or challenges with other cognitive processes, such as language or executive function, affects up to 18% of people age 60 and older. People with MCI maintain most normal daily activities, but are known to be at higher risk of Alzheimer's disease or other forms of dementia. It is estimated that 6.7 million Americans age 65 and older are living with Alzheimer's dementia, with that number expected to double by 2050. The growing prevalence of dementias has given urgency to the search for better and earlier predictors, and targets for treatments that prevent or slow progression. At present, there is only one FDA-approved drug on the market known to even modestly slow symptoms of Alzheimer's in its early stages, and there are no cures or preventives. "Our research shows declining levels of NPTX2 occur many years prior to the emergence of MCI or Alzheimer's symptoms, which raises the possibility of developing new therapeutics that target NPTX2," says Anja Soldan, Ph.D., associate professor of neurology at the Johns Hopkins University School of Medicine and corresponding author of the study. "Additionally, it appears that this protein is not a specific marker to just Alzheimer's, and these findings may be relevant to a variety of other neurodegenerative diseases. So if we can find ways of increasing levels of NPTX2, then it could be applied to identify early and possibly treat other types of memory loss or cognitive impairment as well." For the study, which involved adults recruited by the National Institutes of Health and Johns Hopkins Medicine, researchers conducted baseline medical and cognitive exams on 269 cognitively normal individuals, and collected spinal fluid samples biannually. The average age of participants at baseline was 57.7 years. Nearly all were white, 59% were female, most were college educated and 75% had a close relative with Alzheimer's. NPTX2 levels were measured, as well as the main abnormal proteins found in patients with Alzheimer's, namely beta-amyloid, total tau and phosphor-tau. Subjects underwent clinical and cognitive assessments for an average of 16 years. Results showed: "Currently, we only have drugs that modify mild symptoms of Alzheimer's disease and nothing right now to give people who are cognitively normal but at higher risk," Soldan emphasized. But when and if that changes, Soldan adds, having an accurate way to predict such risk will play a large role in targeting treatments. Soldan also cautioned that "we're a long way out" from a simple way to routinely test spinal fluid samples for NPTX2 levels, and further research is needed to determine what factors alter the protein's levels. Potential root causes could be genetics, lifestyle factors or a combination of them. Soldan also underscored the new study's limitations, including the racial and educational makeup of the study population. Additional authors include Marilyn Albert (principal investigator of the BIOCARD study, from which these data were derived), Sungtaek Oh, Taekyung Ryu, Corinne Pettigrew, Yuxin Zhu, Abhay Moghekar, Mei-Fang Xiao, Gregory Pontone, Chan-Hyun Na and Paul Worley from the Johns Hopkins University School of Medicine. The study was supported by the National Institutes of Health.

Repurposing complement inhibitors to see whether they are effective against neurodegenerative diseases is already in development. With Alzheimer’s disease therapies finally reaching the market and hundreds of active clinical trials for therapies and diagnostics, it seems like every week brings another potential avenue to explore in combating the neurodegenerative disease. The most recent update comes courtesy of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, which pinpointed a brain protein that could offer a fresh target. The development builds on a growing body of work showing that dysregulation of the complement cascade—a set of immune system proteins that protect against infection in the body—in the brain is linked to the cell damage and cell death seen in a range of neurological conditions like Alzheimer’s and schizophrenia. The breakthrough from researchers including at the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard has been to identify neuronal pentraxin protein Nptx2 as a regulator of the complement system in the adult brain. It’s the first time scientists have been able to confirm a brain regulator of the cascade, they wrote in a study published in Science Translational Medicine March 29. Nptx2, which is secreted by excitatory neurons, is already used as a biomarker for a range of neurological disorders. A clue to its potential role is the fact that Nptx2 levels are depleted in the cerebrospinal fluid of patients with Alzheimer’s disease, frontotemporal dementia, schizophrenia and Down syndrome. The researchers used neurodegeneration mouse models to test the effects of boosting Nptx2 levels or blocking complement protein in cells. In one of these mice models, a lack of Nptx2 was tied to increased activity of the complement system as well as the destruction of synapses by the brain’s immune cells. When C1q, the initiating factor of the complement cascade, was eliminated from these animals—either via genetic deletion or with antibody blocking—the researchers noted that synapses in the brain tissue recovered. Similarly, in mice with overactive brain immune cells and high activity of the complement pathway, boosting production of Nptx2 in certain brain cells reversed the loss of synapses. But would the approach also work in humans? To test this out, the researchers assessed levels of C1q and also C3b—an activated complement protein further down the cascade—in symptomatic and presymptomatic patients with genetic frontotemporal dementia. They noted that levels of C1q and C3b were both higher in patients already showing symptoms, while the level of Nptx2 in these patients was lower. An even more intriguing discovery was that Nptx2 bound to C1q was reduced in symptomatic patients, “suggesting that abundant unbound C1q could be driving synapse loss and leading to symptoms of dementia,” according to Broad Institute's press release. “There’s still a lack of understanding of precisely what factors and sequence of events drive neurodegenerative disorders,” the study’s co-senior author Borislav Dejanovic, Ph.D., a scientist in the Stanley Center who is also director of Vigil Neuroscience, said in the release. “Findings like this help us learn what mediates the synapse loss and cognitive decline that is devastating for patients and their families.” Repurposing complement inhibitors to see whether they are effective against neurodegenerative diseases is already in development—for example, Elixiron Immunotherapeutics is testing its CSF1R inhibitor in Alzheimer’s. The work “bolsters the therapeutic strategy of inhibiting the complement pathway, which could one day improve symptoms for patients with neurodegenerative or neuroinflammatory disorders.” “Overall, our study identifies Nptx2 as a neuronal synaptic CCP inhibitor,” the researchers concluded in their study. “Elevating Nptx2 expression might be a viable therapeutic strategy to curb complement overactivation and subsequent neuronal damage in FTD, AD and other neuroinflammatory diseases.”