L3 Neurovascular Degeneration Hypothesis of Alzheimer’s Disease Flashcards
What is neurovascular coupling?
This is a mechanism that ensures oxygen and glucose get to active regions of the brain. A breakdown of this has been linked to AD.
What was one of the first hypotheses of neurovascular coupling and who proposed it?
This hypothesis was proposed by Roy and Sherrington in 1890.
The proposed that the brain possesses an intrinsic mechanism by which its vascular supply can be varied locally in correspondence with local variations of functional activity.
How is neurovascular coupling shown in mordern experiments?
These experiments involve putting people in MRI scanners and giving them a stimulation (such as an image).
The stimulation will cause neural activity which will then, because of neurovascular coupling, will cause vascular changes that can be seen in BOLD (blood oxygen level dependant) fMRI.
What are the two different types of neural activity?
1) Synaptic activity. This is shown by local field potentials (LFPs). fMRI BOLD activity is most correlated with synaptic activity.
2) Spiking activity shown by multi-unit activity (MUA). This activity represents the recorded activity of a population of neurons. This also correlates with fMRI BOLD, but not as well as synaptic activity.
What is fMRI?
Functional MRI. This records the number of blood cells in the brain and if they have oxygen bound to them or not. The fMRI signal is based on changes in deoxyhemoglobin (Hbr).
What causes positive BOLD?
Large increases in blood flow and volume as a result of neurovascular coupling washes away Hbr. The decrease in Hbr levels means less signal attenuation resulting in an increased MRI signal.
Who first proposed the first insight into the role of astrocytes? What did they do?
Zonta et al (2003).
They isolated slices of cerebral cortex and saw that under electrical stimulation of glutamate afferents, neuroncal activation and dilation of arterioles was caused. This was also associated with an increase in Ca within the astrocyte end feet.
This was confirmed by stimulating the individual astrocytes using the patch-clamp technique.
What were the flaws in Zonta et al (2003)’s experiment?
There was no actual blood in their experiment which is not representative of what is happening in the human brain.
Their timings were also wrong - it took up to 30 seconds to get dilation which is far too slow.
Who proposed the prostaglandin pathway and what does this involve?
Zonta et al (2003).
- Glutamate released by an excitatory neuron is taken up by the astrocyte.
- Levels of Ca increase within the astrocyte.
- Molecules such as prostanoids travel towards the feet of the astroctyes.
- When the prostanoids hit the blood vessels they cause them to dilate.
Who provided the first in vivo data of the prostoglandin pathway?
Takano et al. (2006) showed astrocyte-mediated control of cerebral blood flow in mice brains.
The temporal relationship in this study was much better than Zonta et al (2003)’s.
Why do some labs insist the data obtained by Takano et al (2006) is wrong?
They say that the arteries are only dilating because the animal is about to die.
What are the contradicting conclusions concerning neurovascular coupling?
One scientist (Nizar) thinks that the dilation of the blood vessels occurs before the Ca has been released in the astrocyte. Another argues that the dilation is due to the fast responses from the astrocytes.
What are pericytes?
These are cells that wrap around capillaries and are known to have contractile proteins associated with them.
To this day, no one has shown the in vivo role of pericytes.
What did Professor Berislav Zlokovic propose?
The ‘2-hit hypothesis’.
This hypothesis proposes that you get the first hit at the neurovascular unit i.e. there is a breakdown of the blood brain barrier. As healthy brains are always making beta amyloid and washing it away, the brain is not longer able to do this after the first hit so a build-up occurs.
The second hit is the beta-amyloid plaques and the neuropathology that is seen.
The professor believes that pericytes are the main drivers of this process.
What historical problem did Professor Berislav Zlokovic overcome and how?
He overcame the problem that no one type of transgenic Alzheimer’s mouse recapitulates all aspects of the human disease.
He overcame this by taking a Swedish Human APP mutant (this mutant produces beta amyloid plaques and has memory problems, but does not develop tau pathology or neuron loss) and crossing it with a pericyte deficient mouse. The resulting cross’ offspring developed all the characteristics of human AD.
