Biomarkers

Biomarkers

The prospect of immunotherapy for combating Alzheimer’s disease

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Laura Hudson

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BY

Laura Hudson

Alzheimer’s disease is a progressive incurable neurodegenerative disorder that often leads to dementia, loss of motor function and cognitive decline. Current treatment options for Alzheimer’s disease slow the progression of neuronal degeneration and maximise function as far as possible, however, no treatment to date has managed to alter the disease process within the brain.

Accumulation of beta-amyloid plaque deposits and tau protein neurofibrillary tangles are associated with cognitive decline and dysfunction in Alzheimer’s patients. These deposits stimulate localised inflammation in the brain, ultimately leading to neuronal death.  Inflammation in the central nervous system is largely attributed to microglia which, under normal conditions, play an important role in brain development, maturation, and homeostasis. Dysregulated microglial function occurs during aging and in response to neuronal degeneration, and is thought to be the primary contributor to inflammation in neurodegenerative diseases such as Alzheimer’s, as outlined in a recent review published in Annual Review of Medicine 2018 (https://doi.org/10.1146/annurev-med-050715-104343). Although the blood-brain barrier prevents most circulating immune cells from entering the brain, peripheral immune cell influx is possible when this barrier is compromised through infection or neural inflammation. Microglia remain the primary source of high levels of proinflammatory cytokines, including tumour necrosis factor (TNF), interleukin (IL)-1β, and IL-6, that are released in the brain and cerebrospinal fluid of Alzheimer’s patients.

The lymphatic system carries immune cells from the cerebrospinal fluid and connects to lymph nodes, allowing T cells to respond to brain antigens.  In a recent study published in Nature (https://doi.org/10.1038/s41586-019-1895-7), changes in the peripheral immune subsets in patients with Alzheimer’s disease in comparison to matched healthy donors were identified. Most notably, an increase in cytotoxic CD8+ cells in patients with Alzheimer’s disease, as compared to healthy controls, was observed. Effector CD8+ cells were overrepresented in the patient population, with the concomitant underrepresentation of CD8+ memory cells. These results suggest an adaptive immune signature in Alzheimer’s disease, consisting of increased peripheral CD8+ T effector memory CD45RA+ T cells (TEMRA cells – CD3+CD8+CD27-CD45RA+ cells).

Additional investigation highlighted the relationship between cognitive score and T cell subset frequencies. A negative correlation between TEMRA frequency-to-cognition was observed in Alzheimer’s disease. Functional assessments showed TEMRA cells to be more responsive to antigenic stimulation, and to express more pro-inflammatory and cytotoxic genetic markers than healthy matched donors. The upregulated expression of cytotoxic granules, proteases and proinflammatory cytokines, many of which are associated with Alzheimer’s disease, indicate that the peripheral adaptive immune response may play more of a role in Alzheimer’s disease progression than originally thought. This is supported by the discovery of T cells patrolling the intrathecal space of brains affected by Alzheimer’s disease. In light of this, the role of the innate and adaptive immune responses in the setting of neurodegenerative disease is worth investigating.

Synexa Life Sciences has extensive experience in phenotyping both innate and adaptive immune cell subsets. We offer a broad portfolio of customisable functional and immuno-phenotyping assays to characterise immune profiles in various disease states. We have a comprehensive suite of customisable flow cytometry, soluble biomarker and genetic assays at our disposal that can be utilised in the measurement of a multitude of relevant markers in a clinical setting. Additionally, Synexa is part of a well-developed network of collaborating clinicians and clinical sites, with access to patient samples that allow for ProtoTrials™  or pre-clinical research studies, to support drug development or observational longitudinal assays in an in vitro setting.

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