In 1907, Alios Alzheimer published a case study describing an “unusual illness of the cerebral cortex.” The patient presented with rapid memory loss, disorientation in time and space, and behavioral alterations that didn’t fit the criteria for any other disease. Post-mortem analysis showed that the brain under investigation was much smaller than a healthy brain and had deposition of a “special substance” and the presence of fibrils “combined in thick bundles” (1). Today, Alzheimer’s disease (AD) affects an estimated 24 million people worldwide and still lacks an effective treatment (2,3).
Research has revealed that the “special substance” described in the initial publication corresponds to plaque deposits of amyloid beta (Ab) protein and that the “thick bundles” form as hyperphosphorylated tau protein aggregates (4). Both pathophysiological changes contribute to synaptic dysfunction, neurodegeneration, mild cognitive deficit in the early stages of the disease, and dementia in advanced stages (4). However, therapeutic interventions targeting amyloid and tau pathology fail to improve symptoms and prevent disease progression (3). Discovering new factors that contribute to AD pathology is essential for developing new therapies that can improve patients’ quality of life, slow down cognitive decline, increase life expectancy, and reduce caregiver burden.
Keep reading to learn more about recent AD pathophysiology-related discoveries as we kick off Alzheimer’s Awareness Month, and if you're interested in resources for your research, be sure to check out our Resources page.
Bottom Line Up Front
Pre-clinical animal models can be an effective tool to advance the knowledge of the pathophysiology of various diseases. While most drugs tested in animals fail to receive approval for human use, pre-clinical models offer the versatility of bioengineering and genetic manipulations and significantly contribute to advancing the understanding of the mechanisms underlying diseases. Using the triple-transgenic mouse model of AD (3xTg-AD), Brigas et al. reported that the accumulation of IL-17 can be an additional contributor to cognitive deficits in AD (5). The 3xTg-AD mouse model shows a progressive accumulation of amyloid plaques and neurofibrillary tangles, which associates with cognitive decline (6). In their study, Brigas et al. demonstrated that IL-17 accumulation contributes to cognitive decline in a mechanism independent of amyloid and tau pathology.
A Simple Approach to a New Discovery
The research team used the Y-maze and the Morris water maze (MWM) to assess short- and long-term memory, respectively. In the former, the animal navigates a 3-armed maze and uses its short-term (working) memory to avoid entering the last 2 visited arms (7). In the latter, the animal learns and memorizes the location of a hidden platform in a circular pool over a few days (8). By testing the animals at different time points, Brigas et al. categorized the time course of disease progression into 3 phases: Before disease onset (2–3 months old), cognitive decline onset (6–6 months old), and advanced stage with overt pathology and memory deficit (8–9 months). Female mice showed deficits in the Y-maze and MWM at disease onset and advanced stages. However, male mice only showed impairment in the Y-maze test at the later stages of the disease.
Using flow cytometry, Brigas et al. analyzed cells from the brain, meninges, cervical lymph nodes, and spleen. Except for the spleen, all tissue types in 3xTg-AD female mice showed an increased number and percentage of IL-17+ cells relative to control. In addition, an increase in IL-17+ cells was associated with the onset of cognitive deficits and endured into the later stage of AD. Unlike females, male mice didn’t show IL-17+ cell accumulation in any of the tissues analyzed. For this reason, researchers included only females in the subsequent experiments.
As correlation doesn’t imply causation, researchers proceeded to investigate the impact of early IL-17 neutralization on cognitive deficits. A micro-pump delivered anti-IL-17A mAb into the right ventricle for 6 weeks starting at 3.5 months. The intervention prevented deficits in the Y-maze but not in the MWM. Longer administration of neutralizing antibody (3.5–7 months of age) yielded similar results: Short-term memory performance remained intact, but the ability to form long-term memories deteriorated.
Does neutralization of IL-17 prevent amyloid load and tau pathology? Using a Vector® M.O.M.® (Mouse on Mouse) blocking reagent, the investigators were able to use a biotinylated mouse anti-Ab antibody to quantify amyloid protein on mouse brain sections. A sensitive avidin/biotin-based peroxidase system enabled the development of stained sections for quantification of average amyloid plaque size and plaque burden. Accumulation of Ab was similar in anti-IL-17- and control IgG-treated mice. Subsequent western blot experiments revealed similar findings for tau pathology—the neutralization of IL-17 did not affect the levels of total and phosphorylated tau.
Conclusions & Clinical Implications
The findings that accumulation of IL-17 in the brain of 3xTg-AD mice associates with the onset of cognitive decline can have future implications for clinical management of AD. Similar alteration might happen in human AD as patients often present with increased levels of IL-17 in the serum (9). In addition, IL-17 and other pro-inflammatory cytokines increase in the human brain with aging (10). Does IL-17 contribute to cognitive decline in patients with AD? Only future research studies will be able to answer this question. But if new data confirm the role of IL-17 in human AD pathophysiology, this cytokine could serve as a biomarker for early AD diagnosis. Reliable early predictive biomarkers are a crucial need in the clinical management of AD. Although disease-modifying therapies are currently unavailable, focusing on modifiable risk factors such as diet and exercise can delay the development of dementia in some patients. It’s also possible that neutralization of IL-17 in humans could become an effective intervention to prevent the decline of short-term memory in patients with AD. Every discovery, even if small, comes with the hope for better clinical care in the future, but only time will tell the impact of the Brigas et al. study on AD management and treatment.
If you want to learn more about other scientific advances, check out other publication highlights here on the blog, and be sure to stay tuned for more insights that can help improve your results.
- Stelzmann RA, et al. 1995. An English Translation of Alzheimer's 1907 Paper, "Über Eine Eigenartige Erkankung der Hirnrinde." Clinical Anatomy.
- Mayeux R, et al. 2012. Epidemiology of Alzheimer Disease. Cold Spring Harbor Perspectives in Medicine.
- Yiannopoulou KG, et al. 2019. Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research. Biomedicines.
- Tiwari S, et al. 2019. Alzheimer's Disease: Pathogenesis, Diagnostics, and Therapeutics. International Journal of Nanomedicine.
- Brigas HC, et al. 2021. IL-17 Triggers the Onset of Cognitive and Synaptic Deficits in Early Stages of Alzheimer's Disease. Cell Reports.
- Oddo S, et al. 2003. Triple-Transgenic Model of Alzheimer's Disease With Plaques and Tangles: Intracellular Aβ and Synaptic Dysfunction. Neuron.
- Kraeuter AK, et al. 2019. The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice. Pre-Clinical Models.
- Vorhees CV, et al. 2006. Morris Water Maze: Procedures for Assessing Spatial and Related Forms of Learning and Memory. Nature Protocols.
- Chen JM, et al. 2014. Increased Serum Levels of Interleukin-18, -23 and -17 in Chinese Patients with Alzheimer's Disease. Dementia and Geriatric Cognitive Disorders.
- Barrientos RM, et al. 2015. Neuroinflammation in the Normal Aging Hippocampus. Neuroscience.