Characterizing Neuroinflammation to Better Understand Alzheimer’s Disease and Other Neurodegenerative Disorders with Functional Proteomics

As Alzheimer’s and Brain Awareness Month wraps up, we’d like to share how research is advancing the understanding and treatment of Alzheimer’s disease and other neurodegenerative disorders.

Alzheimer’s disease, first described in medical literature over 100 years ago, is the most common form of dementia. Characterized by memory loss and cognitive decline, Alzheimer’s is a debilitating condition for both patients and their families. Although a variety of therapies targeting different disease mechanisms have been tested, there is currently no cure for Alzheimer’s disease. The pathological characteristics of Alzheimer’s disease—neurofibrillary tangles and amyloid plaques—are well known, but scientists are now looking at other mechanisms that contribute to the development of Alzheimer’s disease to identify new targets and improve treatments.

The link between neurodegeneration and neuroinflammation has been of increasing interest for researchers as, though inflammation occurs initially as a protective response, chronic inflammation can be damaging and lead to neuronal loss. Immune profiling, both on the single-cell and population level, can help to elucidate how immune function is altered in Alzheimer’s disease or other neurodegenerative disorders and identify new targets to inhibit maladaptive inflammation.

Identifying Inflammatory Biomarkers of Alzheimer’s Disease and Other Types of Dementia

Because immune cells have numerous functions, single-cell phenotyping can provide detailed analysis about how cell function may be altered by disease state or treatments. IsoPlexis’ Single-Cell Secretome platform, which can measure up to 32 cytokines per cell across thousands of cells in parallel, uncovers how individual immune cells are functioning, giving researchers a better understanding of immune activity. For instance, single-cell analysis of CD8+ T cells from healthy controls were compared with Alzheimer’s disease samples. Results showed that CD8+ T cells from Alzheimer’s samples had more polyfunctional cells (cell secreting two or more cytokines) compared to the age-matched healthy controls. Polyfunctional cells have previously been associated with driving immune response, indicating that immune cells in Alzheimer’s samples may have increased inflammatory activity.

Another type of dementia called frontotemporal lobar dementia (FTLD) was also assessed with single-cell functional proteomic analysis to understand how neuroinflammation contributes to dementia. In this study, cytokine secretion patterns of CD14+ monocytes of FTLD samples were compared with those of healthy controls. FTLD samples exhibited a unique subset of polyfunctional CD14+ monocytes – these findings provide peripheral biomarkers of FTLD and insights into FTLD immune pathology that could contribute to disease progression.

Immune Profiling of Neurodegenerative Disorders

Neuroinflammation has also been implicated in the pathology of other neurodegenerative disorders, including multiple sclerosis (MS). While MS has been identified as an autoimmune disorder, the mechanism of why this occurs is poorly understood. A recent study sought to understand how innate immunity dysregulation may contribute to MS. By using IsoPlexis’ single-cell cytokine analysis platform, researchers were able to show that monocytes from MS samples showed enhanced polyfunctionality and polyfunctional strength index (PSI), the proportion of polyfunctional cells multiplied by the mean intensity of measured cytokines, compared to monocytes from healthy controls. These findings provided unique insights into how immune function is altered in MS.

Cytokine analysis can also demonstrate how inflammation contributes to cognitive dysfunction in COVID-19. IsoPlexis’ CodePlex solution, which enables highly multiplexed cytokine analysis using ultralow sample volumes, helped researchers to profile cytokines in both the cerebrospinal fluid (CSF) and plasma samples to understand the relationship between COVID-19 infection presenting with neurological symptoms and immune function. Compared with healthy controls, the COVID-19 samples displayed elevated levels of IL-6, IL-8, and IP-10. These results provide details about how COVID-19-induced central nervous system inflammation may associate with neurologic manifestations of disease.

Single-Cell Analysis to Characterize Neuroinflammation

The need for better treatment options for neurodegenerative disorders necessitates understanding the underlying contributors to disease pathogenesis, and numerous studies have shown that neuroinflammation contributes to neurodegeneration. Single-cell analysis of immune cells is becoming increasingly important for immune phenotyping of disorders such as Alzheimer’s disease. Recent studies have demonstrated that proteomic analysis specifically can reveal unique insights into mechanisms of progression.

Single-cell immune profiling has already helped researchers to characterize the immune activity contributing to neuroinflammation in Alzheimer’s disease, MS, and COVID-19. By providing deeper insights into drivers of hyperinflammation, single-cell functional phenotyping can reveal unique findings of immune dysfunction in neurodegenerative disorders. With a better understanding of these diseases, researchers can work towards developing new therapies that modify progression of Alzheimer’s disease and other neurodegenerative disorders, ultimately improving patient outcomes and helping those affected by these diseases and their families.

See more insights into neuroinflammation uncovered with functional proteomics in our Neuroinflammation Application Note.

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