Neurodegeneration and Alzheimer's disease

Question 1

What is neurodegeneration

Answer 1

progressive loss of function or structure of neurons

Question 2

What are affected in amyotrophic lateral sclerosis/ motor neuron disease

Answer 2

spinal cord, both lower motor neurons and upper motor neurons are affected, wasting the muscles without innervation

Question 3

Symptoms in ALS/MND

Answer 3

weakness either in the muscles of limbs or in those used in breathing, swallowing or speech
• More muscles are gradually affected until eventually all voluntary movement is lost and death occurs usually for respiratory failure or lung infections

Question 4

What is the cause in ALS/MND

Answer 4

10% is inherited mutation in enzyme superoxide dismutase 1 (SOD1)

Question 5

What will lead to spinocerebellar ataxia and what are the effects

Answer 5

inherited mutation in protein frataxin which lead to neurodegeneration in cerebellum - ataxias

Question 6

Characteristics of Parkinson’s disease

Answer 6

loss of dopaminergic neuron in the substantia nigra (basal ganglia)

Question 7

characteristics of Huntington’s disease

Answer 7

it is caused by CAG repeat in huntington protein causing misfolding of protein and death of inhibitory GABAergic neuron in corpus striatum causing uncontrolled unvoluntary movements

Question 8

How do neurons die

Answer 8

necrotic cell death, apoptosis, autophagy and removing damaged cell can generate further damage

Question 9

What triggers programmed cell death

Answer 9

cellular stress

Question 10

Why is it difficult to observe neurodegeneration in vivo

Answer 10

• Cell does not lyse so difficult to observe ongoing apoptosis
  
  • Diseases manifest with clinical signs only when large part of neurons already degenerated and remaining cells are not sufficient to compensate the loss

Question 11

What is dementia

Answer 11

progressive loss of memory and at least one other cognitive domain, interfering with everyday life

Question 12

What the five types of dementia

Answer 12

Alzheimer’s, vascular dementia, dementia with lewy bodies, frontotemporal degeneration, and association with PD and HD

Question 13

What are the symptoms of AD

Answer 13

impairment of declarative memory, memories of remote past are preserved, , cognitive functions decline and eventually lose language completely

Question 14

Describe the structure of amyloid-B filaments

Answer 14

• flat, pleated domains of different Aβ molecules tend to stick together into aggregates in the shape of fibrils which in turn aggregate in larger, insoluble filaments.

Question 15

Describe the formation of AB

Answer 15

Ab is derived from amyloid precursor protein (APP)

1. Normally APP is cleaved 
2. By enzymes called a- and y-secretases - generating APPsa (trophic and neuroprotective protein)  - Non-amyloidogenic processing
3. And two small peptides whose function is unclear 
4. APP cleaved by b-secretases (BACE1: beta site-APP cleaving enzyme )
5. Generating Ab - Amyloidogenic APP processing

Question 16

Whhat amloid-B exist the most in AD plagues

Answer 16

AB-42, it is more hydrophobic and more prone to aggregate much more easily and more toxic

Question 17

What is the effect of Amyloid-B

Answer 17

Soluble oligomers are the most toxic form and they impair basic neuronal processes. Imbalance between production and clearance of amyloid B leads to accumulation of toxic protein forming neurofibrillary tangles (NFT) and neuronal dysfunction and death. some also say plagues contribute to alzheimers

Question 18

How does Tau hypothesis contributes to Alzheimers

Answer 18

1. Tau normally binds to microtubules and stabilises them
   
   2. Beta amyloid plague initiates pathways that leads to activation of kinase, phosphorylating Tau
   3. Hyperphosphorylated tau has lower affinity for microtubules and does not bind so well. Microtubules depolymerise.
   4. Then hyperphosphorylated tau aggregates and forms paired helical filaments and neurofibrillary tangles.

Question 19

Statements supporting AB hypothesis

Answer 19

• Ab is neurotoxic in vitro
• Ab42 oligomers decrease synapse density and inhibit LTP in rodent hippocampus
• Human Ab42 oligomers induce tau hyperphosphorylation at AD epitopes and cause neuritic abnormalities
• Ab oligomer accumulation appear to precede tau hyperphosphorylation

Question 20

Statements supporting Tau hypothesis

Answer 20

The severity of AD correlates with the amount of NFTs pathology, not with the amount of plaques

NFTs appear first in the medial temporal lobe and then spreads to the associative cortex, in parallel with neuronal and synaptic loss, while plaques appear first in the cortex, and to a lesser extent in the medial temporal lobe.

Some individuals present a heavy Aβ plaque load at death, but no clinical symptoms

Question 21

What will Ab plagues cause

Answer 21

• Can disrupts neuron signalling impairing brain function
  * Start immune response -> inflammation to destroy surround neurons
  * Deposit around blood vessels -> amyloid angiography which weakens the wall of blood vessel and increase the risk of haemorrhage or rupture and blood loss

Question 22

What is the familial cause of AD

Answer 22

caused by mutation in APP, PSEN-1 or PSEN-1 which are components of y-secretase and can produce more AB-42

Question 23

What are the five causes of AD

Answer 23

familial cases, down syndrome, ApoE, and other genes

Question 24

How does Down syndrome contribute to AD

Answer 24

• Gene for APP is on chromosome 21
• Present in three copies in Down’s syndrome
Down’s subjects often present with amyloid plaques

Question 25

How does ApoE contributes to AD

Answer 25

ApoE produces or causes mutation in y-secretase

Question 26

How do you diagnose Alzheimers

Answer 26

presence of plagues of insoluble amyloid-B surrounded by neurites and activated glial cells and tangles

Brain scans:
thinning of gyri and widening of sulci and cerebral ventricles

Question 27

What are the treatment for Alzheimers

Answer 27

Anticholinergics - donepezil, galantamine, rivastigmine and memantine

Question 28

Action of Anticholinergics

Answer 28

they are inhibitors of acetylcholinesterase that breaks down acetylcholine . This supplies for loss of cholinergic neurotransmission in areas affected by AD

Question 29

Action of memantine

Answer 29

it is an inhibitor of glutamate NMDA receptor which is excessively activated in Alzheimers

Question 30

Further directions for treatment for Alzheimers ?

Answer 30

immunotherapy to target Ab, decrease active brain Ab by y-secretase inhibitors, ab aggregation inhibitors,