AD - Tau

Question 1

What are neurofibrillary tangles?

Answer 1

Insoluble aggregates of hyperphosphorylated Tau proteins inside the neurons

Question 2

Which cells normally express tau?

Answer 2

Neurons

found in axons

Question 3

What is the normal role of tau?

Answer 3

Stabilise microtubule integrity and promote microtubule assembly

Question 4

Why does hyperphosphorylation of tau occur?

Answer 4

Inappropriate kinase and phosphatase activity

Overactivity of GSK3beta and Cdk5

Question 5

What are mechanisms through which we think tau leads to neuronal death?

Answer 5

Sequestration > involvement of MAP1 and 2 > polymerisation > tangles > synaptic dysfunction > neuronal death

OR

Sequestration > disassembly of microtubules > disturbed axonal transport > synaptic dysfunction > death

Question 6

How does phosphorylation affect tau functioning?

Answer 6

Impairs its ability to bind to microtubules

Promotes aggregation of tau

Question 7

Where are tau aggregates found?

Answer 7

Cell bodies and dendrites

Question 8

Describe the alterations in KO mice

Answer 8

None? So must be a gain of function mutation

Question 9

Altered tau metabolism is thought to be a secondary effect of….?

Answer 9

Amyloid beta accumulation

Question 10

The current theory of AD involved which pathological processes?

Answer 10

neurofib tangles, plaques, inflammation (from unregulated glia and lipid distribution abnormality) as well as the usual environmental factors and polymorphisms

Question 11

Outline the tau hypothesis

Answer 11

Normal tau ties down microtubules to stabilises then and allow normal axonal transport

Accumulation of phosphate on this causes paired helical filaments to accumulate and then leads to neurofib tangles

Impaired axonal transport and neuronal death occurs

Question 12

Which theory is preferred and why?

Answer 12

Plaques bc transgenic mice with mutant APP develop plaques, not tangles