Inflammation and cognition: a closer look at early Alzheimer’s disease
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is associated with immense loss of cognitive function, particularly memory loss. Over 700,000 Canadians are living with dementia, including AD, and over 44 million people worldwide.
The brain is composed of a combination of gray matter, where the processing happens, and white matter, which connects different gray matter regions to each other. Scientists have been studying AD for over a century, with much of the focus being on the gray matter, yet we still lack effective treatments. More recently, disruption to the white matter has been related to cognitive deficits early in AD, including deficits in a set of cognitive skills collectively known as executive function.
Executive function refers to a group of mental processes required for goal-oriented behaviours. Some examples include: planning, organization, and cognitive flexibility. Previously, a team of researchers at Western University showed that an AD rat model exhibits cognitive inflexibility and increased inflammation in the white matter. However, the age-related changes in cognitive decline and inflammation had not been assessed. Recently, Western University researchers assessed cognition and white matter inflammation across aging and AD in a rodent model. The 2021 study published in Molecular Neurobiology was led by Dr. Alexander Levit, an MD/Ph.D. graduate in Dr. Shawn Whitehead’s laboratory. To carry out this study, the researchers used a genetically modified rat model of AD. This model was chosen because it exhibits brain pathology that represents early AD.
Cognitive flexibility is an important subdomain of executive function that refers to one’s ability to switch strategies. For example, you are planning to walk to work, but it begins raining just as you leave the house. By deciding to bring an umbrella, wear a raincoat, or drive, you are exhibiting cognitive flexibility. To test cognitive flexibility, the rats were placed in a box with two levers, a light above each lever, and a food trough. The rats had to learn that when a light turned on above a lever, they should press that lever to receive a food reward. Once this strategy was mastered, the rules changed, and only one of the levers would result in a food reward. The rats’ ability to make this switch was assessed as an indicator of cognitive flexibility. The researchers evaluated rats from 4 to 22 months of age and found cognitive flexibility deficits as early as 8 months in the AD rats, roughly equivalent to young adulthood.
Next, the researchers wanted to assess memory loss, another debilitating symptom of AD. To do this, they used a task called the Morris water maze. The goal of this task was for rats to use their surroundings to locate a submerged platform in a pool. Their ability to learn the location of this platform was assessed, and then their ability to remember it. Dr. Whitehead’s team found that the AD rats exhibited learning and memory impairments but that this came much later in disease progression than the cognitive flexibility deficits.
Finally, the researchers sought to investigate the progression of white matter brain inflammation in this AD model. Microglia are brain immune cells that account for about 10-15% of cells in the brain, and under healthy conditions, are critical for brain maintenance. Microglia become activated in response to injury or disease and are essential mediators of inflammation and recovery. However, they can impair normal brain function if they remain activated for too long. The researchers quantified activated microglia in white matter brain regions and found that this increased with normal aging and was intensified in the AD rats. Similar to the deficits in cognitive flexibility, the increase in white matter inflammation also began early in disease progression.
Overall, Dr. Whitehead’s team revealed distinct cognitive and pathological changes over time in a rodent model of AD. Understanding the cognitive changes that occur across aging in AD is critical to both identifying those at risk of severe dementia and developing treatments for such individuals. The authors point out that further studies are needed to understand if white matter inflammation is contributing to cognitive decline. Scientists have been studying AD for over a century, but our understanding of the disease is still developing. Preclinical models, such as the AD rat model used in this study, are critical steps to learning about disease mechanisms and treatment possibilities.
Original article: Levit, A., Gibson, A., Hough, O., Jung, Y., Agca, Y., Agca, C., Hachinski, V., Allman, B.L., Whitehead, S.N. (2021) Precocious White Matter Inflammation and Behavioural Inflexibility Precede Learning and Memory Impairment in the TgAPP21 Rat Model of Alzheimer Disease. Molecular Neurobiology. 58:5014-5030
https://link.springer.com/article/10.1007/s12035-021-02476-w