Metals

Question 1

What does the accumulation of metal ions in human brain depend upon?

Answer 1

Pre-existing vascular disease, environment, high metal diet.
Neuro effects of air pollution as humans can take up metals via olfactory bulb / nerve.

Question 2

Why is early life exposure to metals important?

Answer 2

Hare et al 2015
BBB leaky in early life promoting movement of hydrophilic components into brain.
High iron diet when young can predispose to dementia later in life.
This vascular dementia can the promote more metal movement.
Vulnerability window may operate in first 5 years of life.

Question 3

Give three roles of copper in the body excluding PAM?

Answer 3

Nt biosynthesis
CuZnSOD
Dopamine levels
noradrenaline synthesis

Question 4

What is PAM and how is it linked to copper?

Answer 4

Enzyme essential fro synthesis of all AMIDATE neuropeptides; neuropeptide Y, Substance P (pain), Gastrin, Pancreastatin (insulin control).
Highly conserved copper dependent enzyme.

Question 5

How does Zinc function in the brain?

Answer 5

as an essential neuromodulator and a potent neurotoxin.

Background levels = 3nM, excitatory are 10,000 times that

Question 6

How is Zinc-altered in Alzheimer’s disease?

Answer 6

Increase in mRNA of ZnT1, 4, 6, 7 and Zip1 in AD CORTEX.
Decrease in ZnT-3 mRNA in AD cortex.
Zn can be detected in amyloid plaques

Question 7

How does iron cross the BBB?

Answer 7

Cross luminal membrane of the capillary epithelium by receptor-mediated endocytosis of ferric Tf.
Within ISF iron binds any unsaturated Tf.
Ferric Tf taken up by neurones and glial cells by receptor-mediated endocytosis.

Lf = more tolerant of acidic pH and binds 1 Fe!

Question 8

What form of metals must be seen in disease to demonstrate a pathological effect?

Answer 8

Catalytically active forms not associated with major transport / storage proteins.

Question 9

What is iron required for in the brain?

Answer 9

Myelin synthesis
Thy1 synthesis (nt release)
Developmental processes in hippocampus.
NM synthesis.

Question 10

What are the characteristics of Alzheimer’s disease?

Answer 10

Amyloid protein deposition in senile plaques
Intraneuronal inclusions of proteins such as hyperphosphorylated tau
Glial activation around plaques and Neuton death.