neurodegenerative dementia Flashcards
what is dementia
a global impairment of higher cortical function wihch is usually progressive and irreversible
main symptoms of dementia
short term memory loss, day to day problem solving skills, perceptuomotor skills, social skills and emotional reactions
Common types of dementia
AD - progressive starting with memory
Vascular dementia - caused by impaired blood supply, sudden or step wise symptoms, variable cognition problems
FTD/PICKS - younger diagnosis. Progressive symptoms but not memory just higher cognitive function
Dementia with lewy bodies - rapid fluctuations in cognitive ability, hallucinations, motor defects occasionally
Protein inclusion as markers of neurodegeneration
AD - amyloid plaques, NFT
FTD - somtimes tangles
D with lewy bodies - lewy bodies
PICKS - pick bodies and cells
AD symptoms
deficits in memory function
disruption of normal daily living/social skills intact
LT memory failure
deficits in higher cognitive functions
spatial and temporal disorientation
dyspraxia
apathy, depression, agitation, anxiety, paranoia, delusions
how is brain affected pathalogically in AD
Apathy, narrowed gyri, increased sylvian fissure, global shrinkage, widened sulcal margins.
what areas of brain are affected by AD
Frontal lobe, parietal lobe and temporal lobe including hippocampus
What are markers for AD
Amyloid plaques and NFTs. often activated glia
What are NFTs composition
teardrop shaped tangles due to hyperphosphorylated tau filling pyramidal cells
What are Amyloid plaques composition
Contained in neuropil and made of 7-10nm thick protein fibres with amyloid Beta peptides and degenerative nerve endings
Causes of AD
94-99 idiopathic.
1-6% mendelian genetic inheritance
Key markers for diagnosis of AD
pupil dilation test with tropicamide unusually fast
altered CSF tau (high) and low AB proteins
the mini mental state exam
post mortem is definitive
AD therapies
Cholinesterase inhibitors - donepezil, galantamine, rivastigmine
Partial NMDAr antagonist - memantine
Cholinesterase inhibitor mechanism
inhibits AchE in cleft so Ach present for longer and not degraded as quickly. acts in septum pellucidum –> hippocampus, and nucleus of meynert –> widespread cortical connections
partial NMDAr antagonist mechanism
low affinity uncompetitive NMDA antagonist, binding to open conformation. limits excitotoxicity and alters aberrant synaptic plasticity
Hypothesis causes of AD
cholinergic dysfunction, glutamatergic dysfunction, amyloid, tau
What is normal mechanism of APP processing and how is it altered in AD
a secretase to release APP, y secretase to release beneficial p3.
b secretase instead of a in AD. AB then released instead of p3
where does a secretase cut
amino acid 17
where does b secretase cut
1/11
where does y secretase cue
40/42
what is the gene for a secretase
ADAM 10/17
What is the gene for b secretase
BACE - 1
What are the proteins that make up y secretase
presenelin 1/2, nicastrin, aph1 and pen2
What do APP mutations cause
increase b secretase cleavage - EOAD
what do PSEN1/2 mutations cause
increase y secretase activity - EOAD
what is the old hypothesis for AD and who came up with it
Hardy and HIggins, 1992. Amyloid cascade hypothesis –> amyloid leads to NFT and cell death
Genetic evidence for amyloid hypothesis
Familial Mendelian AD is linked to mutations in APP, PSEN1 and 2
ApoE isoform 4 is predisposing to EOAD
What is ApoE4 and what does it do
lipid transporting protein that can assist in clearance of AB. isoform 4 not as effective
How is familial mendelian AD linked to mutations in APP, PSEN1 and 2
EOAD. increase in AB1-42 and AB1-40
includes trisomy of chromosome 21 where APP gene is located
what is most toxic form of AB
AB-1
what does APP do
alters neuronal excitability
protective functino recently found
what is APPswe
EOAD mutation
what does APPswe do
not active - no calcium measure shown. increases l type ca currents. APPswe mouse has defects in neuronal structure. Spine number decreased close to plaques
what is tau
microtubule associated protein which stabilises
What does tau do in disease
hyperphosphorylate
dissociate from microtubules
misfolding and aggregation into NFTs
how is tau hyperphosphorylated
upregulation if kinases or down regulation of phosphatases
Tauopathy pathology
no plaques but cell death
in rTg4510 model of tauopathy, what is mutated?
P301L mutation in MAPT gene found in FTDP-17
does AB in brains always cause cognitive impairments?
no
soluble or plaques as better indicator?
soluble as better correlation to decline in cognition
what does soluble AB on cultured neurons cause
EPSC reduction
what is first thing that AB affects?
synaptic transmission
what does APP mutation not do?
produce amyloid
Mutated APP with GFP experiment results and problems
APP mutation doesnt produce amyloid.
overexpression so may not be related to disease
AB is usually extracellular whereas intra in experimenty
do AB transgenic mice studies influence tau formation?
yes
what is the relationship between microglia and AB?
microglia found near plaques and directly activated by AB
what is TREM2
genetic factor for AD which may lead to activated microglia
what is the structure of AB fibirls
s shaped stack formed by AB1-42 but not AB1-40. conformation of monomers different
main issues of b secretase inhibitors?
pharmacokinetics
y secretase inhibitor problems
accelerated cognitive decline as no p3. also targets notch
potential mechanism of y secretase modulators
preferential AB38>42 without notch 1 cleavage
what is solanezumab
monoclonal antibody directed to mid section of AB. failed phase 3
