Neuroprotection Flashcards
what is a protected cell?
one protected from amyloid
what are three main goals of neuroprotective strategies?
prevent
cure
halt
what is a neurotrophin
NGF
mediates survival via activating TrkA and p75
what do we know for certain about neurotrophins- NGF?
certain neurons- specifically cholinergic neurons in the forebrain- rely on NGF for survival during survival
what is the cholinergic hypothesis?
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
describe cholinergic pathway in AD patients
increased amyloid beta-> less ach-> have pro-ngf but not processed correclty into mature ngf and so neurons killed off
describe relationship of ach and NGF
more ach = more cell survival
what does NGF promote and maintain?
survival and maintains the phenotype of cholinergic neurons in vitro- so treating ad patients with ngf may improve cholimergic function and memory
what is the potential of ngf for ad?
neuroprotective agent
what are the problems with ngf for ad treatment?
massive and cannot cross the BBB easily
what are the three main methods of ngf into patients?
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
what was the results of trial to administer NGF to AD patients
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
what is predicted longterm for future ngf treatment
5 years post treatment- robust outgrowth
10 years post treatment- still continuaiton of mgf
what is GDNF
glial cell line derived neutrophoc factor
a potent neurotrophin for midbrain dopaminergic neurons
describe GDNF with ad
protective of toxins related to pd
what is the amgen double blind trial?
GDNF delivered into brain surgically and no benefits after 6 months
trial halted due to conspiracies when patients developed anti-gdnf antibodies
what are delivery options for gdnf
gene therapy- no benefit
encapsulated genetically modified cells
perfusion pump devision- no benefit
what is leptin
an antiobesity hormone which prevents neuronal death
what does leptin do?
prevents upregulation of p-tau and endophilin 1 (AD biomarkers)
what happens if there is no leptin
early degenerative changes ar synapses and so cell communication is poor
why would leptin be a good drug?
gathering evidence that it counteracts AD pathology at multiple levels
already licensed for obesity
well tolerated
why would leptin be a bad drug
bery big molecule
hard to move across BBB
cost
what is the SAM cycle for
disease prevention
what is the SAM cycle
methionine metabolism recylcing
adenosylmethionine is most common way to methylate DNA
must undergo transition to be methyl donor
donates group -> homocystein
what is a homocytein
not good
lots of it is an AD risk factor
what does homocytein do
initates oxifative stress
damages blood vessels
