The Human Cerebellum May Protect Itself Against Alzheimer’s

 Xu et al. "Regional protein expression in human Alzheimer’s brain correlates with disease severity." Communications Biology (2019)Cerebellum (Latin for "little brain") in green. Cerebellar means 'relating to or located in the cerebellum.' Source: Xu et al. "Regional protein expression in human Alzheimer’s brain correlates with disease severity." Communications Biology (2019)

A massive database of region-specific protein expression in six functionally distinct regions of the Alzheimer’s brain—including the hippocampus, cingulate gyrus, entorhinal cortex, sensory cortex, motor cortex, and cerebellum—is now available online for anyone to access. This “dementia proteomes project” was led by Richard Unwin from The University of Manchester.

The full details of this study, “ Regional Protein Expression in Human Alzheimer’s Brain Correlates with Disease Severity ,” were published online February 4 in Communications Biology .

“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. It could also help validate observations seen in animal or cell disease models in humans,” Unwin said in a statement. “It’s very exciting to be able to make these data public so scientists can access and use this vital information.”

The primary goal of this research was to use Liquid Chromatography-Mass Spectrometry (LC-MS) on post-mortem human brain samples and compare protein expression levels in six brain regions between individuals with Alzheimer’s Disease (AD)-affected brains to the same brain regions in age-matched controls without AD.

The authors explain the design and significance of their study:

“The current study aims to overcome some existing limitations by providing a spatially resolved analysis of protein expression in six regions of human control and AD-affected brain, reflecting varying levels of ‘affectedness,’ in well-matched, short post-mortem delay tissue. Briefly, we quantify over 5000 proteins in AD and control tissue, to our knowledge the most in-depth study of this type to date.

These data reveal protein changes between AD and control tissue, which appear to form a gradient through the brain, in order of affectedness where less affected regions display a smaller subset of those changes seen elsewhere, possibly representative of an early disease state. We also show that [human] cerebellum, rather than being unaffected by AD, displays a pattern of protein expression changes distinct from other brain regions, which could be protective for this region of the brain.”

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In my opinion, the most noteworthy aspect of this research is that the human cerebellum displays a pattern of regional protein expression that is mysteriously distinct from the other five brain regions analyzed for this study.

According to the researchers, although the cerebellum can contain amyloid plaques, the so-called "little brain" is generally considered by most experts to be one region of the whole-brain that is typically ‘spared’ by Alzheimer’s.

As Unwin explained, “The cerebellum, previously thought to be unaffected [by Alzheimer's], displays a significant response at the molecular level. Many of the changes here are not seen in other regions and this could imply that [the human cerebellum] actively protects itself from Alzheimer’s disease. We won’t know for sure until we carry out more research.”

The million-dollar question: Why does the human cerebellum in an otherwise AD-affected brain display a significantly lower level of ‘affectedness’ by Alzheimer’s disease? The University of Manchester researchers speculate that a distinct protein expression profile and "upregulated neuronal survival pathways" may be associated with unique neuroprotective functions in the “little brain.”

In their paper, first author Jingshu Xu and her co-authors do a deeper dive into surprising ways that the human cerebellum (CB) may protect itself against Alzheimer’s:

“One of the most distinct changes observed in this cerebellum-specific analysis was that a much greater number of proteins of electron transport chain (ETC) complex 1 were consistently more reduced in abundance than was found in other areas. Furthermore, CB showed increases in oxidative defence proteins involved in glutathione redox reactions and ascorbate recycling. These data provide strong additional evidence for a protective mechanism in CB that decreases reactive oxygen species (ROS) production by ETC while simultaneously increasing ROS defenses. Another interesting observation in CB was the activation of a purine ribonucleosides degradation pathway, which could not only contribute substrate to the pentose phosphate pathway, but also participate in guanine/guanosine production in this brain region.

Cerebellum does not display extensive apoptotic activation seen elsewhere in the brain in AD, which is unsurprising given its structurally unaffected status. Our findings indicate that the lack of significant neurodegeneration in this region is not merely due to the absence of an apoptotic signal (e.g., Tau tangles) but instead that cerebellum actively induces a unique pattern of upregulated neuronal survival pathways alongside protection against oxidative and inflammatory damage; a protective mechanism of gene/protein expression, which limits disease-related degeneration in this region.”

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Of course, much more collective thinking and expanded research is needed to fully understand how the human cerebellum may protect itself against AD-related degeneration. Thankfully, Unwin and his UK-based team are eager to promote worldwide sharing and usage of all their data.

Hopefully, any cerebellum or dementia research scientists reading this post will take advantage of the searchable web interface that hosts the database from the latest University of Manchester study ( Xu et al., 2019 ) at www.manchester.ac.uk/dementia-proteomes-project .