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Dementia is a complex and progressive disease scientists are trying to find treatments for. Yagi Studio/Getty Images
  • The accumulation of deposits of the beta-amyloid and tau proteins in the brain is a hallmark of Alzheimer’s disease and is associated with disruption of communication between neurons and cognitive decline.
  • However, some individuals showing an aggregation of these Alzheimer’s-associated pathological proteins are resilient to deficits in cognitive function and are referred to as having asymptomatic Alzheimer’s.
  • A recent study has identified a protein called neuritin in the brains of individuals with asymptomatic Alzheimer’s that may help preserve the structure of synapses—the connections between neurons in the brain—and, subsequently, confer resilience to cognitive decline.
  • The study’s results suggest that this protein could serve as a therapeutic target to prevent the progression of Alzheimer’s in vulnerable individuals.

A commonly used approach for identifying treatments for Alzheimer’s disease involves the use of cell culture and animal models in the initial stages to identify therapeutic targets, followed by clinical trials to examine whether these findings can be reproduced in humans. However, this approach has often resulted in failure of treatments in clinical trials.

Another approach involves conducting an observational study to identify a potential therapeutic target in humans. This is followed by conducting experiments using cell culture or animal models to validate the molecule’s therapeutic effects and examine the mechanisms underlying these therapeutic effects. The molecule can then be tested in clinical trials, and such an approach is considered to be more successful.

A recent study published inMolecular & Cellular Proteomics used this novel approach to identify a protein—called neuritin—that could preserve cognitive function in individuals showing pathological changes in the brain associated with Alzheimer’s.

The study’s co-author Dr. Nicolas Seyfried, a professor at Emory University, told Medical News Today that one of the mysteries and “the most pivotal, unanswered questions in the field” was how cognitively healthy older adults with the pathological signs of Alzheimer’s disease withstood the onset of dementia.

“Communication among neurons through synapses is required for cognitive function in humans. Cognitive impairment in Alzheimer’s disease is the result of synapse loss in brain regions that are critical for memory processes. Therefore, the ability to maintain cognitive abilities in an environment of Alzheimer’s disease pathology must be linked to the preservation of synapses in resilient individuals,“ Dr. Seyfried explained.

“Using innovative and integrated systems biology to study neurons and synapses in human aging, we made a discovery that the protein neuritin is critically important to maintain resilience in cognitively [healthy] patients with Alzheimer’s disease pathology.”
— Dr. Nicolas Seyfried

“By identifying neuritin, we can now study neuritin in experimental models in order to design therapeutics based on neuritin’s role in resilience to Alzheimer’s disease,” added Dr. Seyfried.

Alzheimer’s disease is characterized by the accumulation of misfolded aggregates of beta-amyloid and tau proteins. These deposits are associated with the disruption of the normal functioning of synapses, the specialized junctions where neurons communicate with each other. The release of neurotransmitters at the synapse helps to relay electrical impulses from the axon of one neuron to another neuron’s dendrite and then on to the neuron’s cell body.

In addition to deficits in synaptic function, the accumulation of beta-amyloid and tau proteins in Alzheimer’s disease is associated with the loss of dendritic spines in brain regions involved in cognition. Dendritic spines are small protrusions on the dendrites which contain excitatory synapses.

The accumulation of beta-amyloid and tau deposits and other brain changes occur gradually over several years before the manifestation of symptoms of cognitive decline.

However, some individuals with high levels of these protein deposits, in particular beta-amyloid, do not eventually show deficits in cognitive function. Previous studies have shown that these resilient individuals with asymptomatic Alzheimer’s do not show a loss of neurons or a decline in synaptic function.

The study’s co-author Dr. Jeremy Herskowitz, a neurologist at the University of Alabama at Birmingham, explained: “Research progress has provided avenues to detect Alzheimer’s disease pathology in living humans and yielded evidence that the pathologic events of [Alzheimer’s] initiate years to decades prior to dementia onset.”

“Yet, many older individuals without dementia or mild cognitive impairment meet the pathologic criteria for [Alzheimer’s]. These cognitively normal individuals with [Alzheimer’s] pathology are, by definition, in the preclinical stages of [the disease], yet in life, they appear resilient to dementia,” he elaborated.

However, the molecular mechanisms underlying this resilience to cognitive impairment are not well-understood. In addition, most studies focused on understanding pathways underlying resilience to AD-related cognitive impairment have focused on changes in the dorsolateral prefrontal cortex, a brain region involved in executive functioning.

Yet numerous other brain regions involved in cognition also show an accumulation of beta-amyloid and tau proteins. In the present study, the researchers examined whether individuals with asymptomatic Alzheimer’s also showed changes in protein expression in other brain regions, similar to those observed in the dorsolateral prefrontal cortex.

Specifically, they focused on Brodmann Area 6 (BA6) and Brodmann Area 37 (BA37), which are involved in language processing and cognition. In individuals with Alzheimer’s, BA6 predominantly shows an accumulation of amyloid plaques, whereas BA37 mostly shows aggregates formed of tau protein.

In the present study, the researchers first examined whether individuals with Alzheimer’s disease and those with asymptomatic Alzheimer’s disease showed differences in protein expression in the BA6 and BA37 regions.

The study used post-mortem brains obtained from 109 individuals participating in the Religious Orders Study and Rush Memory and Aging Project (ROSMAP project). The Religious Orders Study and the Rush Memory and Aging Project are separate longitudinal studies aimed at identifying risk factors associated with dementia.

Both studies included participants without dementia at the time of enrolment and involved annual assessments to evaluate the cognitive function of the participants over time.

The group of ROSMAP participants included in the study consisted of individuals without Alzheimer’s, those with Alzheimer’s, and those with asymptomatic Alzheimer’s. These individuals were categorized into these three groups according to the changes in cognitive function over time and post-mortem levels of beta-amyloid and tau deposits in their brains.

The researchers compared the protein expression patterns in these three groups. The researchers found differences in protein expression in BA6 and BA37 among the three groups, with a greater number of proteins differentially expressed in BA37 than in BA6.

The researchers then identified modules or clusters of proteins whose expression patterns were correlated across both regions in all participants. The simultaneous changes in the expression of proteins belonging to a specific cluster suggest that they are potentially co-regulated and may work together to perform a specific function in the cell.

They found 39 such clusters of co-expressed proteins in the BA6 and BA37 regions. Most of these modules were also found in a previous study that characterized the protein expression profile of the dorsolateral prefrontal cortex in individuals with AD.

Five out of the 39 protein clusters showed a positive correlation with cognitive function and were associated with disease status.

Specifically, participants with asymptomatic Alzheimer’s showed increased expression of proteins in five modules in the BA6 and BA37 regions than those with symptomatic Alzheimer’s.

Another two protein expression modules were negatively correlated with cognition and showed higher expression levels in symptomatic AD than in asymptomatic cases.

Given the decline in synaptic function in Alzheimer’s disease, the researchers focused on two modules containing proteins associated with synaptic function. These protein modules were among the five clusters associated with slower cognitive decline.

While proteins in these modules were independently associated with cognitive resilience, the protein neuritin (NRN1), also known as the cpg15 gene, showed a strong correlation with slower cognitive decline. Previous studies have shown that NRN1 plays a role in the maturation of synapses and in maintaining brain plasticity.

The expression levels of NRN1 in both BA6 and BA37 were associated with overall cognition and changes in cognitive function over time. In addition, NRN1 levels in these brain regions in individuals with asymptomatic AD were similar to those without AD but greater than participants with AD.

Notably, NRN1 levels could explain the degree of difference in cognitive function among individuals to a significant extent, thus demonstrating the central role played by this protein in influencing cognitive function and decline.

The accumulation of beta-amyloid protein in animal models of Alzheimer’s disease is associated with the loss of dendritic spines in regions involved in cognition. Thus, mechanisms that prevent the loss of dendritic spines could help maintain cognitive function in resilient patients.

In the present study, the researchers examined whether NRN1 protein could exert protective effects against the effects of beta-amyloid protein in cell culture experiments.

The researchers cultured cells from the rat hippocampus, a brain region involved in learning and memory, and exposed these cells to either NRN1 or beta-amyloid protein alone or together. Exposure to the beta-amyloid protein resulted in the loss of dendritic spines on hippocampal neurons, and the combination of NRN1 with beta-amyloid prevented the loss of these spines.

The loss of dendritic spines and reduction in the surface of the neurons in Alzheimer’s disease is associated with excessive activation of neurons, subsequently leading to impaired cognitive function. Exposure of rat hippocampal neurons to beta-amyloid led to excessive activation of neurons, whereas the use of NRN1 with beta-amyloid prevented excessive activation of neurons.

Researchers examined the changes in protein expression patterns in rat neurons after exposing them to NRN1. the results suggested that the NRN1 protein increased the expression of proteins associated with synaptic processes and cellular projections such as axons or dendrites.

Moreover, NRN1 exposure also reduced the expression of proteins associated with cellular metabolism and other energetic processes. This finding is consistent with other studies showing disruption of metabolic processes in Alzheimer’s disease.

Lastly, the researchers examined how NRN1 could influence protein expression in neurons in individuals with asymptomatic Alzheimer’s. Hence, they compared the protein expression modules in primary cultures of rat neurons after exposure to NRN1 with those found in individuals with Alzheimer’s.

There was considerable overlap in protein expression profiles in rats and humans, with 17 out of the 39 modules in humans also found in rat neurons. In addition, four human protein modules associated with synaptic function showed increased expression in rat neurons after exposure to NRN1.

Notably, most of the proteins showing increased expression in rat neurons after NRN1 exposure were also upregulated in the brains of individuals with asymptomatic AD. These results suggest that the NRN1 pathway could potentially contribute to resilience against the cognitive deficits observed in AD.

The study’s authors intend to further examine the basic biology of the NRN1 pathway and whether NRN1 in biological fluids could serve as a marker of cognitive resilience.

Dr. Clifford Segil, a neurologist at Providence Saint John’s Health Center in Santa Monica, California, told MNT that the study brought a new perspective to current research.

“The goal of identifying something in people’s brains to promote memory retention rather than a pathological condition that worsens memory loss is novel and a pleasure to learn more about. More often, the focus of research papers is on pathological hallmarks of the disease, and this paper focuses on something to promote cognitive resilience of healthy aging,” he said.

“Proteins were identified by these researchers, which may be a marker of healthy aging, which could protect from memory loss and cognitive complaints [associated with Alzheimer’s] rather than worsening these conditions.”
— Dr. Clifford Segil