Neuroprotection

Question 1

what is a protected cell?

Answer 1

one protected from amyloid

Question 2

what are three main goals of neuroprotective strategies?

Answer 2

prevent
cure
halt

Question 3

what is a neurotrophin

Answer 3

NGF

mediates survival via activating TrkA and p75

Question 4

what do we know for certain about neurotrophins- NGF?

Answer 4

certain neurons- specifically cholinergic neurons in the forebrain- rely on NGF for survival during survival

Question 5

what is the cholinergic hypothesis?

Answer 5

pathways which show decline in AD patients are cholinergic
we have neurons in nuclease basilis with trka as neurotrophic receptor
in cerebral cortex one pathway is to produce NGF and ach is stimulus
pro ngf is processed to mature ngf and must form ot make a dimer

Question 6

describe cholinergic pathway in AD patients

Answer 6

increased amyloid beta-> less ach-> have pro-ngf but not processed correclty into mature ngf and so neurons killed off

Question 7

describe relationship of ach and NGF

Answer 7

more ach = more cell survival

Question 8

what does NGF promote and maintain?

Answer 8

survival and maintains the phenotype of cholinergic neurons in vitro- so treating ad patients with ngf may improve cholimergic function and memory

Question 9

what is the potential of ngf for ad?

Answer 9

neuroprotective agent

Question 10

what are the problems with ngf for ad treatment?

Answer 10

massive and cannot cross the BBB easily

Question 11

what are the three main methods of ngf into patients?

Answer 11

systemic- conjugated to cross BBB or intraventricualr administration of ngf
grafting brain tissue that secretes ngf- model animals
using viral vectors, transfected cell lines or biomaterials engineered to secrete NGF

Question 12

what was the results of trial to administer NGF to AD patients

Answer 12

given intraventricular ngf
but had to stop trial before end as caused severe back pain
ngf leaked into spinal fluid, NGF signals as pain when released due to trka expressed on surface of 50% nociceptors

Question 13

what is predicted longterm for future ngf treatment

Answer 13

5 years post treatment- robust outgrowth

10 years post treatment- still continuaiton of mgf

Question 14

what is GDNF

Answer 14

glial cell line derived neutrophoc factor

a potent neurotrophin for midbrain dopaminergic neurons

Question 15

describe GDNF with ad

Answer 15

protective of toxins related to pd

Question 16

what is the amgen double blind trial?

Answer 16

GDNF delivered into brain surgically and no benefits after 6 months
trial halted due to conspiracies when patients developed anti-gdnf antibodies

Question 17

what are delivery options for gdnf

Answer 17

gene therapy- no benefit
encapsulated genetically modified cells
perfusion pump devision- no benefit

Question 18

what is leptin

Answer 18

an antiobesity hormone which prevents neuronal death

Question 19

what does leptin do?

Answer 19

prevents upregulation of p-tau and endophilin 1 (AD biomarkers)

Question 20

what happens if there is no leptin

Answer 20

early degenerative changes ar synapses and so cell communication is poor

Question 21

why would leptin be a good drug?

Answer 21

gathering evidence that it counteracts AD pathology at multiple levels
already licensed for obesity
well tolerated

Question 22

why would leptin be a bad drug

Answer 22

bery big molecule
hard to move across BBB
cost

Question 23

what is the SAM cycle for

Answer 23

disease prevention

Question 24

what is the SAM cycle

Answer 24

methionine metabolism recylcing
adenosylmethionine is most common way to methylate DNA
must undergo transition to be methyl donor
donates group -> homocystein

Question 25

what is a homocytein

Answer 25

not good

lots of it is an AD risk factor

Question 26

what does homocytein do

Answer 26

initates oxifative stress

damages blood vessels