Ageing brain 02/04

Question 1

Which two neurotransmitters show the greatest age related decline?

Answer 1

Glutamate

Ach

Question 2

What are the main gross pathological changes in the brain with ageing?

Answer 2

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.

Question 3

What are the main causes of cell atrophy?

Answer 3

1. Blood flow decline
2. Mitochondrial dysfunction
   decreased ATP and increased ROS
   - decreased synthesis of proteins & growth factor receptors
   - excitotoxicity
   - Inflammation
3. Accumulation of damaged/misfolded proteins

Question 4

3 main factors contributing to decreased blood flow

Answer 4

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.

Question 5

How does CVD contribute to reduced blood flow in the brain?

Answer 5

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.

Question 6

How does mitochondrial dysfunction cause brain atrophy?

Answer 6

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.

Question 7

How does mitochondrial dysfunction alter syanpses formation?

Answer 7

1. Increased ROS production leads to nuclear DNA damage and there is less production of ATP
2. Less growth factors and receptors are synthesised (both decline with age)
3. There is reduced gene expression and protein synthesis for formation of synapses, cell growth, damage repair etc

Question 8

What is the role of oestrogen on brain ageing?

Answer 8

Oestrogen encourages growth factor production and synapse formation. Premenopausal women show delayed brain ageing.

Question 9

What are three immediate consequences of reduced ATP production during reduced blood perfusion?

Answer 9

1. Sodium handling
2. Calcium handling
3. Glutamate excitotoxicity

Question 10

How does sodium handling change in reduced blood perfusion?

Answer 10

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.

Question 11

How does calcium handling change in reduced blood perfusion?

Answer 11

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.

Question 12

How does glutamate excitotoxicity occur in reduced blood perfusion?

Answer 12

1. Calcium causes the release of excitatory neurotransmitter glutamate.
2. Glutamate causes the membrane to depolarises more. Glutamate receptor (NMDA) is activated.
3. 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.

Question 13

How may AGEs contribute to AD?

Answer 13

AGEs pentosidine and GLAP have been shown to be increased in AD patients.

1. Glycation of amyloid beta enhances plaque formation
2. AGE activates BACE-1 by RAGE -NFkB pathway to enhance amyloid production
3. AGEs increase ROS and oxidative stress, increasing AB formation

Question 14

How can diabetes increase Ab pathology?

Answer 14

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

Question 15

How does tau phosphorylation relate to synaptotoxicity?

Answer 15

Microtubule destabilisation results in decreased growth factor transport to terminals where it may be released. This leads to neural atrophy and death

Question 16

How do amyloid and tau interact and converge onto apoptotic pathways?

Answer 16

Amyloid beta accumulates in the mitochondria, causing cytochrome c release which activating capsases leading to cell death.
It also activates kinases which phosphorylate tau.

Hyperphosphorylated tau causes loss of spines and synapses and eventually cell death.

Question 17

What are caspases?

Answer 17

family of protease enzymes playing essential roles in programmed cell death (apoptosis)

Question 18

What do normal ageing and AD brains have in common?

Answer 18

Mitochondrial dysfunction

increase ROS

Reduced growth factors effects

Poor blood flow

Loss of synpases in the dentate gyrus. This may account for one of the cognitive abilities that declines in old age - spatial memory.

Question 19

How are reduced growth factors related to changes in blood flow?

Answer 19

Simplified example is that reduced BDNF receptor activity results in less production of Vascular endothelial growth factor, resulting in shrinkage of the vascular bed.

Question 20

How does the ageing brain differ from the alzheimer’s brain?

Answer 20

There is very little cell death observed in normal ageing. This is because the normally aged brain still retains plasticity. It appears that the ageing brain has compensatory reponses, which are lost in AD. This is through:

•Healthy neurones growing their dendrites: Dendrites grow around areas of neuronal death to contact healthy neurones further away, new synapses made

•Using other brain areas: Dendrite growth allows recruitment of other brain areas. For example, older people show loss of hemispheric asymmetry and broader prefrontal activation during fingering tapping tasks.

•Stem cell proliferation

Question 21

Why do stem cell proliferation occur in normal ageing but not in AD?

Answer 21

Stem cells from the hippocampus and the ventrical linings migrate to areas such as the substantia nigra, cortex and olfactory bulb. They can then differentiate to give rise to new neurons.

This is all under the control of growth factors. Grow factor receptor density is reduced in AD compared to normal ageing.

Question 22

How can stem cell neurogenesis be increased?

Answer 22

Experiments in rats show:
- Exercise and enriched environments

- Pregnancy, increased oestrogen and prolactin

- Growth factor supplmentation (IFG, BDNF)

Neurogenesis reduced by: glucocorticoids, stress

Question 23

What effects has exercise been shown to have on the brain?

Answer 23

In addition to neurogenesis experiments in rats have shown:

increased Brain and blood IGF-1 and BDNF

increasedgrowth factor expression in hippocampus = reverse cell atrophy

increased Brain Capillary density

increased antioxidant glutathione peroxidase

reduced oxidative stress

Question 24

How is normal memory loss distinguished from pathological memory loss?

Answer 24

Degree of impairment and the rate of cognitive decline.

In AD, there is a signficant loss of volume in the entorhinal cortex (this correlates with degree of cognitive decline) , which is not observed in normal ageing.

Altered brain activation on functional imaging and the appearance of early pathological changes in medial temporal lobe (including entorhinal cortex) structures may distinguish incipient dementia from normal aging

Question 25

How does gene expression change in ageing?

Answer 25

Microarray studies from 6 species (including humans) have found two things common to gene expression changes in all species.

1. There are changes, but these age-related expression changes account for only a small fraction of the genes. This suggests that there is not simply a genome wide dysregulation, but that very specific biological pathways are changing.
2. There is an age-associated induction of stress response genes
3. There is a reduction in the expression of mitochondrial genes, which may underlie the stress response.

Question 26

What age gene expression changes have been found in humans?

Answer 26

1. Downregulation of genes involved in synpatic plasticity. These include glutamate receptor subtypes
2. Upregulation of genes involved in stress responses​. These include antioxidant defense, DNA repair, and immune function

Question 27

What is the relationship between hippocampal neurogenesis, astrocytes and ageing?

Answer 27

While astrocytic density remains constant with age, as shown by GFAP staining in the hippocampus. However, their secretion of proneurogenic growth factors declines and this correlates with the degree of hippocampal neurogenesis.

Astrocytes minimally secrete BDNF, and while this does not decline, the density of BDNF growth factor receptor does decline. The levels of BDNF correlate with memory and hippocampal volume in older people.