B7.051 Neurodegenerative Disease Flashcards
definition of neurodegenerative disease
progressive decline in a neurologic function or functions, arising from neurodysfunction that eventually includes neuron loss/death
are neurodegenerative disorders primary disorders of neurons
not always
can be astrocytes or microglial cells
subjective cognitive impairment
patient believes they have cognitive impairment
not observable by physician
mild cognitive impairment
patient believes they have cognitive impairment
changes observable by physician
not enough impairment to interfere with daily life
dementia
cognitive decline that impacts ADLs and is recognizable by physician
different syndromes associated with neurodegenerative disorders
cognitive/behavior movement strength coordination spasticity
anatomic locations of neurodegenerative disorder focus
cortex white matter cerebellum spinal cord peripheral nerve by system (motor, basal ganglia, vision, hearing, autonomic, transmitter)
histopathological classes of neurodegenerative diseases
amyloidoses tauopathies synucleinopathies TDP43-opathies prion disorders
what is an amyloid
B sheet configured peptide
green birefringence on congo red staining
common synucleinopathies
Lewy body diseases
- lewy body dementia
- parkinson’s
secretases associated with APP
a, B, y secretase
all cut at different locations on APP
from top to bottom: B site, a site, y site
non-amyloidogenic processing of APP
- a secretase cleaves
- soluble APPa
- APP-CTF83 in membrane - APP-CTF82 is cleaved within the membrane by y secretase
- AICD (amyloid intracellular domain)
- P3
amyloidogenic processing of APP
- B secretase cleaves
- sAPPB
- APP-CTF99 - APP-CTF99 is cleaved within the membrane by y secretase
- AB : goes on to form plaques
- AICD
characteristics of AB protein
can be in an a or B conformation, B sheet high probability
central hydrophobic cluster
highly hydrophobic region
fold in order to sequester the hydrophobic region from the aqueous environment
transformation of AB protein into plaque
oligomers (2-12 amyloid pieces)
fibrils of multiple oligomers
plaque of multiple fibrils
are AB plaques toxic?
unclear
- could be toxic to the extracellular environment
- AB proteins themselves could be transported into cell and be toxic to intracellular components
- may not be toxic at all
how does an AB oligomer become alternatively folded
random nucleation event
-thermodynamically unfavorable refolding
what happens as a result of alternative folding
alternatively folded oligomers coerce other members of protein family to fold in the same manner (“seeding”)
standard oligomers drawn into alternatively folded conformation
fibril formation
what happens with lengthening of an alternatively folded fibril
changes from soluble to insoluble
insoluble fibrils aggregate to form plaque
diagnosis of neurodegenerative disease
clinical syndrome neuroimaging CSF biomarkers blood biomarkers genotyping
CSF biomarkers in alzheimer’s
b amyloid decreases
tau protein increases
AB/tau ratio examined
relevant alzheimers genotyping
presenilin 1
presenilin 2
APP
treatment approaches for neurodegenerative disease
supportive symptomatic disease modifying prevention -primary -secondary
most common rate of neurodegenerative changes
insidious/chronic
cognition/ behavior neurodegenerative diseases
Alzheimers
frontotemporal dementias
prior disorders
lewy body dementia
movement neurodegenerative diseases
parkinsons lewy body dementia progressive supranuclear palsy corticobasal degeneration MSA huntingtons
strength neurodegenerative diseases
ALS
coordination neurodegenerative diseases
spinocerebellar ataxias
spasticity neurodegenerative diseases
hereditary parapareses
amyloid neurodegenerative diseases
alzheimers
tau neurodegenerative diseases
frontotemporal dementias
progressive supranuclear palsy
corticobasal degeneration
a synuclein neurodegenerative diseases
Parkinson’s
lewy body dementia
MSA
TDP43 neurodegenerative diseases
ALS
frontotemporal dementias
