Scientists in the U.K. and New Zealand are making freely available the results of what they claim is the largest ever map of protein expression in the human Alzheimer’s disease (AD) brain. Reported in Communications Biology, the study (“Regional protein expression in human Alzheimer’s brain correlates with disease severity”), which charts AD-related changes in the expression of more than 5000 proteins across six different brain regions, has identified dozens of proteins that had not previously been linked with the disease, and finds unexpected changes in one area of the brain that may be protective. The overall results will hopefully provide new insights into Alzheimer’s disease progression at the pathway and molecular level, as well as indicate new drug targets and therapeutic approaches.

map of human Alzheimer’s brain
Source: The University of Manchester

“This database provides a huge opportunity for dementia researchers around the world to progress and to follow-up new areas of biology and develop new treatments,” commented research lead Richard Unwin, PhD, at the University of Manchester. “It could also help validate observations seen in animal or cell disease models … It’s very exciting to be able to make these data public so scientists can access and use this vital information.”

AD is a neurodegenerative disorder that manifests as progressive dementia, and affects an estimated 36 million people around the world, the researchers wrote. However, there is currently no effective treatment that can hold back AD progression. The disease is characterized by the accumulation of Aβ peptide and microtubule-associated protein tau in the brain. The resulting amyloid plaques and neurofibrillary tangles of hyperphosphorylated tau that develop are thought to be central to disease pathology, but what scientists don’t yet understand is the nature of the mechanisms that underpin the disease process. “There remains a lack of detailed mechanistic knowledge about what happens in the human brain in AD,” the team stated. The situation is further complicated because different brain regions are affected at different times as the disease progresses, and this can’t be recapitulated in cell culture models. Animal models also fail to mirror the complete disease process.

To try and generate a more comprehensive picture of AD progression at the protein level, the researchers compared the expression of 5825 distinct proteins in normal brain tissue and in AD brain tissue that had been donated by patients at the New Zealand Brain Bank in Aukland. Relative changes to levels of each protein were measured across each of six different brain regions—the hippocampus (HP), entorhinal cortex (ENT), cingulate gyrus (CG), motor cortex (MCx), sensory cortex (SCx), and cerebellum (CB). “These regions were selected to represent parts of the brain known to be heavily affected (HP, ENT, CG), lightly affected (SCx, MCx), and relatively ‘spared’ (CB) during the disease process,” they stated. Each brain region was analyzed in isolation, “adding strength to our comparison of protein expression changes across multiple regions, since these were identified and quantified independently.”

Overall, the team was able to quantify 4835 distinct proteins in at least one brain region. Among these, 3302 were common to at least three brain regions, and 1899 to all six regions. The analyses generated some 24024 data points.

When compared with protein expression in control brain tissue, the most severely affected regions in the AD brain tissue included, as expected, the hippocampus, entorhinal cortex, and cingulate gyrus, which showed changes in the expression of approximately 30% of proteins that could be quantified. The motor cortex and sensory cortex showed far fewer changes (11–13% of proteins).

The results identified 128 proteins—including 44 that hadn’t previously been linked with AD—that were differentially expressed in at least 5 of the 6 brain regions.  “This subset was selected as these proteins are guaranteed to be changed in at least one of MCx and SCx, and as such likely also represent changes, which occur earlier in disease, and are thus more interesting from a therapeutic targeting perspective,” the researchers commented. Hundreds of other proteins were changed only in the late-affected regions. “These new protein changes represent further targets for scientists developing new drugs,” Unwin stated.

A big surprise was that there were changes to the expression of 20% of proteins in the sixth brain region, the CB, which has previously been thought to be unaffected by AD. “Strikingly, the CB, which many think to be pathologically ‘unaffected’, shows a substantial number of protein changes,” the authors wrote. The changes were also distinct from those seen in the other three regions that are most affected.  “Our data strongly suggest that the CB is heavily affected by AD at the molecular level, at least in late stage disease … That the changes in CB are different from those seen elsewhere in the brain raises the possibility that, rather than being ‘spared’, the CB is affected in a different way to other brain regions and that, given it shows little pathology, these changes may reflect some level of active protection.”

Further analyses highlighted a number of biological pathways that were affected by AD, and in particular pathways involved with the innate immune response. “In AD, aggregates of Aβ can trigger both pathogen-associated and initiate immune responses, and a persisting elevation of Aβ may elicit a chronic reaction of the innate immune system,” the researchers suggested. “In this study, we observed strong evidence for the global activation of the innate immune response, including of the acute phase response, the complement system (classical and alternative pathways), and the coagulation system, consistent with widespread neuroinflammation, suggesting that this may be a relatively early (prior to atrophy) event in pathogenesis.”

Pathway-level analysis also identified Wnt signaling pathways, and those involved in apoptosis and cell cycle regulation, as being widely dysregulated in the most severely affected regions of the AD brain, and there was evidence of both global and regional metabolic defects. “Defects in brain metabolism and energetics are central to the pathogenesis of AD as evidence by epidemiological, neuropathological, and functional neuroimaging studies,” the authors pointed out.

Interestingly, correlation network analysis identified four candidate genes, syntaxin binding protein 1 (STXBP1), collapsin response-mediator protein 1 (CRMP1), actin-related protein 10 homologue (ACTR10), and amphiphysin (AMPH), which might explain a “significant portion” of the protein expression response to AD, the scientists further noted. “Our finding that these four genes appear to be central to various pathological processes known to be involved in AD development is important, and suggests that further work should be performed to focus on the role of these potentially key mediators of AD progression.”

The team concluded that the study’s findings offer up new insights into the brain region specificity of AD both at the level of individual proteins, and at the level of pathways. “An association between extent of molecular changes and affectedness was observed for five regions, allowing us to delineate probably ‘early’ and ‘late’ changes in protein expression and revealing previously novel involvement of several pathways and processes,” the group noted. “The sixth region, CB, showed an unexpectedly distinct pattern of protein changes, suggestive of induction of a protective response.”

“We think that the changes we see in the regions affected later on represent early disease changes, present before cells die,” Unwin said. “These represent good new targets for drug developers, as we know it’s important to try to intervene early.”

“By studying thousands of individual proteins, this exciting research has generated a detailed molecular map of changes that get underway in the brain in Alzheimer’s disease,” commented Rosa Sancho, PhD, head of research at Alzheimer’s Research UK. “Making this information freely available online will help researchers to navigate the complex and changing environment of the brain in Alzheimer’s and identify processes that could be targeted by future drugs. There are over half a million people in the U.K. living with Alzheimer’s and there are currently no treatments that can slow or stop the disease from progressing in the brain. Pioneering research like this is driving progress towards new breakthroughs that will change people’s lives.”

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