human lupus autoantibodies against nmda receptors mediate cognitive impairment
DESCRIPTION
Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Kowal et al. Proceedings of the National Academy of Science PNAS: vol. 103 (52) no. 53, pp.19854-19859 Mentor: Bruce T. Volpe Affiliation: Burke Cornell Medical Research Institute - PowerPoint PPT PresentationTRANSCRIPT
Human lupus autoantibodies against NMDA receptors
mediate cognitive impairment
Czeslawa Kowal, Lorraine A. DeGiorgio, Ji Y. Lee, Mark A. Edgar, Patricio T. Huerta, Bruce T. Volpe and Betty Diamond
Kowal et al. Proceedings of the National Academy of SciencePNAS: vol. 103 (52) no. 53, pp.19854-19859
Mentor: Bruce T. VolpeAffiliation: Burke Cornell Medical Research Institute White Plains, NY
What does the title mean?
• Lupus: a disease in which some antibodies of a person damage the kidney, skin and brain.
• Autoantibodies: (auto=self) they work against the organs of the same person that produced them.
• NMDA receptors: proteins in the membrane of some some neurons that bind with the neurotransmitter glutamate.
• cognitive impairment: (cognition= to know) when a person has severe difficulties knowing and remembering events
INTRODUCTION
Lupus: • first discovered in the middle ages, Latin for wolf.
• The name refers to the skin of the sufferer which turns
red in the final stages of the disease.
• In adults, out of 10 patients 9 are women
• Children with lupus die very quickly because it destroys the cells of the heart.
NMDA receptors in the brain
presynaptic axon
NMDA receptor
AMPA receptor
postsynaptic dendrite
GLUTAMATE
spine
• Stimulated NMDA receptors allow for Calcium to enter the neuron • Over-stimulated receptors lead to cell death
Autoantibodies:
• They are produced by B cells of the immune system just
like normal antibodies .
• They “go rogue” and attack the organs of the person who
made them as if the organs were foreign pathogens.
• Several hundreds of autoantibodies have been described, each defining its own disease.
In Lupus, the autoantibodies target the NMDA receptors in the brain.
In Lupus the autoantibodies target the NMDA receptors in the brain.
Blood-brain barrier (BBB): • A selectively permeable layer around each blood vessel
in the brain.
• It only allows oxygen, glucose and very small molecules
like amino acids to enter the brain.
• Antibodies never naturally cross the blood brain barrier because they are large.
Conditions that rupture the BBB:
1. High levels of stress
1. Bacterial infections
2. Recreational drugs – Smoking– Methamphetamines (crystal meth)
PROBLEM:
The hypothesis of the study is:
• the lupus autoantibodies are in the blood
• They only cross through the blood brain barrier when it is ruptured.
• Once in the brain they bind to areas rich in NMDA receptors
• Once bound the NMDA receptors they cause severe neuronal damage.
METHODS:
• A dying lupus patient donated her brain to scientific research.
• The authors extracted the autoantibodies from the blood and the brain of the patient.
• They injected the antibodies into a group of mice (experimental group)
• An inactive antibody was injected into a second group (control group)
• An infectious agent was given to all the mice to break the BBB
• The mice underwent a learning test to check their memory
• The brains of the mice were analyzed for stress and dead cells
CONTROL GROUP
CONTROL ANTIBODIES(from brain of Parkinson’s patient)
LUPUS BRAIN& LUPUS BLOOD
LEARNING TASK IN CYLINDER WITH COLD WATER AT THE BOTTOM
EXPERIMENTAL GROUP
AUTO-ANTIBODIES
MOUSE BRAINS ARE EXTRACTED AND EXAMINED FOR DAMAGE
BLOOD-BRAIN BARRIER IS BREACHED WITH INFECTIOUS AGENT
RESULTS:1. The lupus autoantibodies extracted from the blood (Anti-NMDAR Serum) bind
to the NMDA receptor
2. The lupus autoantibody (Anti-NMDAR Serum) produces cognitive impairment, measured as slower learning in the circular water chamber
3. The lupus autoantibody (Anti-NMDAR Serum) damages neurons that are rich in NMDA receptor
EXPERIMENTALWithout BBB breach
White cells are damaged cells
CONTROL EXPERIMENTALWith BBB breach
DISCUSSION:
• When the BBB is broken the autoantibodies cause severe neuronal damage to the brain.
• The important part of the brain that is primarily attacked it the Hipocampus
• Damage to the Hippocampus causes cognitive impairment and memory loss.
CONCLUSIONS:
• The authors found that Lupus autoantibodies only cause damage when the BBB is broken and that once they enter the brain they target the hippocampus and other important sectors of the brain.
FUTURE RESEARCH:
1. Further research on the cure to Lupus (inhibiting the rogue antibodies or making the NMDA receptors resistant to the autoantibodies)
2. Applying the cognitive impairment test used on mice to other diseases that effect the brain.
3. Finding a way to repair or enhance the BBB.
CITATIONS:
• Kowal et al. Proceedings of the National Academy of Science PNAS: vol. 103 (52) no. 53, pp.19854-19859
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