The ageing brain Flashcards
Which two neurotransmitters show the greatest age related decline?
Glutamate
Ach
What are the main gross pathological changes in the brain with ageing?
Cortical and hippocampal atrophy. Hippcampus recieves incoming Ach projections and sends outgoing glutamatergic projections to the cortex. Therefore gross pathological changes are associated with NT changes.
A very small number of cells die - atrophy is mainly accounted for by synaptic loss and cell shrinkage.
Women lose 15% of brain volume, men lose 20% of brain volume.
What are the main causes of cell atrophy?
- Blood flow decline
-
Mitochondrial dysfunction
decreased ATP and increased ROS
- decreased synthesis of proteins & growth factor receptors
- excitotoxicity
- Inflammation - Accumulation of damaged/misfolded proteins
3 main factors contributing to decreased blood flow
There is a global reduction in blood flow with age.
Density of capillaries decreases by 10-20%
Basement membrane thickens - longer diffusion distance
Reduced cholinergic vasodilatation
These all result in reduced glucose and oxygen reaching neuronal cells and glia.
How does CVD contribute to reduced blood flow in the brain?
Atherosclerosis is a build up of plaques made up of fat, cholesterol and calcium in the arteries. Lipid build up in the arteries restricts blood flow to the brain, reducing cerebral perfusion. This can lead to a stroke. Very small infarcts are found increasingly with age.
How does mitochondrial dysfunction cause brain atrophy?
Throughout the rest of the body, damaged mitochondria accumulate and result in cell death - however these cells can be replaced. This does not occur within the brain. Not only this but neuronal mitochondrial operate at much higher levels of activity due to increased demand for energy within the brain and these mitochondria therefore die much more quickly due to increased ROS production.
How does mitochondrial dysfunction alter syanpses formation?
- Increased ROS production leads to nuclear DNA damage and there is less production of ATP
- Less growth factors and receptors are synthesised (both decline with age)
- There is reduced gene expression and protein synthesis for formation of synapses, cell growth, damage repair etc
What is the role of oestrogen on brain ageing?
Oestrogen encourages growth factor production and synapse formation. Premenopausal women show delayed brain ageing.
What are three immediate consequences of reduced ATP production during reduced blood perfusion?
- Sodium handling
- Calcium handling
- Glutamate excitotoxicity
How does sodium handling change in reduced blood perfusion?
Reduction in ATP means that Na/K ATPase cannot restore the potassium gradient. Intracellular Na+ builds up - chloride and water therefore follow electrical and osmotic gradients into the cell. The cell begins to swell and may burst.
How does calcium handling change in reduced blood perfusion?
The membrane depolarises due to reduced activity of Na/K pump.
Voltage-dependent Ca channels open
Ca enters, activates proteases, lipases and nucleases.
This can result in cell digestion.
How does glutamate excitotoxicity occur in reduced blood perfusion?
- Calcium causes the release of excitatory neurotransmitter glutamate.
- Glutamate causes the membrane to depolarises more. Glutamate receptor (NMDA) is activated.
- More calcium enters cell through glutamate receptor.
The increased calcium causes cell death.
This depolarising wave caused by glutamate release can spread to other cells.
How may AGEs contribute to AD?
AGEs pentosidine and GLAP have been shown to be increased in AD patients.
- Glycation of amyloid beta enhances plaque formation
- AGE activates BACE-1 by RAGE -NFkB pathway to enhance amyloid production
- AGEs increase ROS and oxidative stress, increasing AB formation
How can diabetes increase Ab pathology?
Hyperglycaemia leads to enhanced AGE production
Increased sugar levels leads to increase glycation of AB and enhanced plaque formation
Increased insulin levels also stimulate release of amyloid by neurons.
Increase insulin competes with AB for degradation by insulin degrading enzymes
How does tau phosphorylation relate to synaptotoxicity?
Microtubule destabilisation results in decreased growth factor transport to terminals where it may be released. This leads to neural atrophy and death