SfN18: New strategies for identifying causes of vascular dementia

Written by Sharon Salt, Editor

Studies that link breakdowns in the brain’s blood vessels to Alzheimer’s disease (AD) and vascular dementia were presented at SfN Neuroscience (3–7 November 2018, San Diego, CA, USA). Researchers anticipate that molecules that signal damage in these systems could aid in earlier detection of these diseases and inform more effective interventions.
The research presented at the conference reveals new mechanisms for how damage to the brain’s vascular system contributes to neurodegeneration and point towards potentially protective or therapeutic interventions, such as exercise.

Biomarkers for brain vascular injury could help identify dementia in its early stages

In the first study presented, researchers report that people at genetic risk for AD have elevated levels of molecules that signal brain vascular injury at early stages of cognitive impairment. This finding could help in earlier detection of the disease, and also in identifying targets to slow its progression.

Although the accumulation of misfolded proteins such as amyloid-β and tau in the brain are hallmarks of disease progression in AD, there are no robust biomarkers for early detection and intervention, which could help people with the disease and also serve as an evaluative tool for clinical trials.

In this study, researchers collected CSF from 268 older human volunteers, some of which carried the APOE4 allele. The team found more molecular markers of injury to the blood–brain barrier and vasculature in the CSF of individuals with mild cognitive impairment, compared with those who had no impairment.

The molecules included proteins that would not usually cross an intact blood–brain barrier, and were further evaluated in the volunteers who carry the APOE4 allele. Amyloid-β and tau were not elevated in these individuals.

These findings suggest that breakdowns in the blood–brain barrier occur before amyloid-β and tau proteins can be detected in the CSF, and that biomarkers of vascular damage might be better targets for early detection of dementia.

“To identify biomarkers for this kind of vascular damage offers a useful way to detect AD earlier and could help us to target novel treatments to delay, slow and ultimately prevent the disease,” commented Berislav Zlokovic (University of Southern California, CA, USA).

Cardiovascular exercise may protect against vascular impairment in mouse model

A second study has identified that regular, moderate levels of exercise may prevent memory problems and white matter inflammation in a mouse model of vascular dementia. The research suggests that vascular disease could be slowed or prevented by increasing cardiovascular fitness.

In this research, investigators put mice on a high-cholesterol diet, which has previously been shown to trigger memory problems in rodents. Some of the mice had a genetic defect in their brain vasculature, which made them particularly susceptible to the cholesterol’s ill effects.

Half of the mice on the high-cholesterol diet were then given access to running wheels each day. After 3 months, the researchers tested the animals’ spatial memory, working memory and object recognition memory. They found that mice that had been eating the high-cholesterol diet without running on the wheels struggled with memory tests, whilst those that had exercised performed much better – even including mice with the genetic defect.

Lianne Trigiani (McGill University, Canada), first author of the study, concluded: “We know that late-onset dementia is related to vascular diseases. If we can reduce the risk of this vascular disease developing through exercise and cardiovascular fitness, we could reduce the number of people developing dementia.”

A molecule depleted in vascular dementia could be used for early detection or treatment

A third study has reported that people with vascular dementia have abnormally lower levels of a fatty molecule that contributes to neuron survival in their blood. This research may lead to the development of a blood test to predict dementia risk and suggest a potential strategy to prevent cognitive decline.

S1P is a fatty molecule that controls many brain functions, from the developing and survival of neurons, to the activation of glial cells. In order to determine whether the molecule is linked to dementia, researchers compared plasma from people with vascular dementia and AD to that of healthy individuals.

People with vascular dementia had low levels of C16-S1P, a variant of S1P. The team performed a series of tests on this variant and found that it could reduce inflammatory processes associated with dementia. Following this, the team plan to explore whether low C16-S1P can predict the development of vascular dementia before symptoms are observed, and if reactivating C16-S1P can reduce or prevent cognitive decline.

“This research identifies a process that could drive vascular dementia. Future efforts will determine whether tests for this molecule could be sensitive enough to predict dementia before the onset of symptoms, or to help distinguish between vascular dementia and AD in order to give appropriate treatment,” concluded Deron Herr (University of Singapore).

The role of the brain’s waste-disposal system in neurodegeneration

In this fourth study, scientists have revealed that loss of function in the lymphatic vessels occurs with age, limits brain waste clearance and may contribute to some neurodegenerative disorders. The study, which investigated lymphatic dysfunction in mice, could aid efforts to develop therapies that stave off age-related brain disorders such as AD.

Researchers used drugs, surgery and genetic manipulations to interfere with drainage by these channels in mice. Compared with healthy controls, mice without functional lymphatic vessels did worse on learning and memory tasks. Reduction of lymphatic drainage in mutant mice that mimic familial AD also showed worse buildup of amyloid plaques.

In contrast, boosting the function of lymphatic vessels improved waste clearance from the brains of old mice, and improved their performance on the cognitive tests.

Jonathan Kipnis (University of Virginia, USA), concluded: “Our results suggest that the decrease in CSF drainage by the lymphatic system affects brain function. We believe that improving lymphatic function in aging patients could help delay or prevent the neurodegeneration seen in AD.”

Watch more from Jonathan Kipnis on discovering the brain’s lymphatic system here.

Neurobiology of the strongest genetic risk factor for AD

In this last study, the mechanism behind the strongest genetic risk factor for AD is described. This study was conducted in mice and indicated how APOE4 worsens regional brain microcirculation and blood–brain barrier integrity, and leads to neuronal loss and cognitive decline.

Scientists imaged the rains of old transgenic mice carrying or not carrying APOE4 before and after they died. In the APOE4 mice, the blood–brain barrier was leakier compared with mice who didn’t have the mutation. The APOE4 mice had more pathological deposits of amyloid in their brain tissue, suffered more microbleeds in the brain, and also showed decreased cerebral blood flow.

Together these effects led to severe neuronal loss, brain atrophy and loss of cognitive functions in the mice. This work suggests that APOE4 drives pathological changes in the brain’s protective barrier, which may ultimately lead to the neuronal loss and decline seen in people with Alzheimer’s.

“We are beginning to understand the neurobiology of this risk factor and the changes it drives. Our latest findings reinforce the need for an effective treatment for Alzheimer’s patients, based on the APOE4 gene and its protein,” explained Berislav Zlokovic.

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Sources:

  1. Pachicano M, Sweeney MD, Sagare AP et al. Impact of APOE4 genetic risk on neurovascular unit biomarkers in early cognitive dysfunction. Programs and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 9502).
  2. Trigiani LJ, Lacalle-Aurioles M, Bourourou M et al. Benefits of exercise on cognition and white matter pathology in a mouse model of vascular cognitive impairment and dementia. Programs and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 6469).
  3. Herr DR, Chew WS, Lai MKP. Non-canonical structural variants of sphingosine 1-phosphate are altered in the plasma of patients with vascular dementia, but not with Alzheimer’s disease. Programs and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 10259).
  4. Da Mesquita S, Louveau A, Vaccari A et al. Meningeal lymphatic vessels play a key role in age-dependent cognitive decline and in Alzheimer’s disease pathology. Programs and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 3205).
  5. Montagne A, Barnes S, Lawson E et al. Amyloid-independent cerebrovascular dysfunctions in age humanized APOE4 targeted replacement mice. Programs and Abstracts of SfN Neuroscience 2018. San Diego, CA, USA, 3–7 November 2018 (Abstract 3178)