Neurodegeneration Flashcards
neuropathology of alzheimer’s disease
Extracellular plaques (accumulation of protein in parenchyma)
Neurofibrillary tangles (disruption of neural cytoskeleton)
Cerebral amyloid angiopathy (CAA)- Same as in brain Protein can be found in bv
Neuronal loss (cerebral atrophy) – supporting feature – not dx
senile plaques - alzheimer’s
Plaque protein – brown – B amyloid protein
cerebral amyloid angiopathy
B-amyloid protein
what is the APP structure
AB protein also known as b amyloid
AB is Part of the precurser protein APP – cleaved from it
AB is what forms the pathology
how is APP processed
normal processing of APP - cleavage happens within the AB sequence
pathologically -AB is removed from the precurser -> when AB accumulates -> plaques
what is toxic in alzheimer’s
Plaques are actually a result of smaller amounts of AB intracellularly – that are then kicked out as a coping mechanism forming plaques.
Cell death due to disruption of intracellular processes. not due to the plaques
Also there is the tangle formation intracellular – potentially small AB promote break down the intraneuronal cytoskeleton
Tau is the cytoskeletal protein
abnormal form is stained by Antibody - shouldnt see this brown
what is Braak staging of tau
Dx alzheimers at post mortum
Everyone >60 will show signs of Alzheimers in brain
It depends on amount and where – stage based on where Tau protein has got to and how much there is
what is aducanumab
anti AB drug - to help slow alzheimer’s
approved by FDA
not approved here yet
neuropathology of parkinson’s disease
Lewy body – inclusion in pigmented cell in the substantia nigra in the brain stem - Projections to basal ganglia – control movement
locus classicus
Black is neuromelanin – help control and initiate movement
Can loose 60-70% of cells before become symptomatic
what are lewy bodies
eosinophilic inclusions
here they are in pigmented neurons - nigra neurons
how is a-synuclein related to parkinsons disease
mutations in the α-synuclein gene can result in PD
Lewy bodies and Lewy neurites are immunoreactive for α-synuclein
Now α-synuclein immunostaining is the diagnostic gold standard
a-synuclein deposits have been found in peripheral autonomic ganglia esp in gut, also epicardial
may be helpful as early biomarker for parkinsons - allowing therapy
Pathology also found in the nose – could be an env toxin acting on genetic susceptibility – spark pathological cascade
what is the staging for parkinsons
Braak stages
6 stages - starts in medulla, up throughh pons, to basal foreframe, limbic system, out to cortex
End stage parkinsons and florid cognitive sx wil have a lot of pathology in cortex
causes of parkinsonism
Idiopathic Parkinson’s disease
Drug-induced Parkinsonism
Multiple system atrophy
Progressive supranuclear palsy
Corticobasal degeneration
Vascular pseudo-parkinsonism – can mimic parkinsons if in the basal ganglia
Alzheimer’s changes
Fronto-temporal neurodegenerative disorders
20 other disorders
have to look out for the green ones - different lesions associated with them
what is multiple system atrophy
can look like parkinsons
also an a-synucleinopathy but it is in the glial support cells not the neurons
what is Corticobasal Degeneration(CBD)
astrocytic plaques are Tau proteins
what is progressive supranuclear palsy
vertical eye movement problems. But can have it w/o eye problems.
Tau problem
what is progressive supranuclear palsy
vertical eye movement problems. But can have it w/o eye problems.
Tau problem
what is pick’s disease
Fronto-temporal atrophy
Marked gliosis and neuronal loss
Balloon neurons
Tau positive Pick bodies
Most common fronto-temporal dementia
what is the tau structure
Single gene on 17q21
16 exons (exons are tau binding domains)
Alternative splicing gives rise to 6 isoforms
3R or 4R-tau (microtubule-binding domains)
Two further inserts with unknown function
Shortest form (3R/0N) foetal
molecular diagnosis of tau diseases
Some are due to problems with 4R tau, some 3R tau – some with both
Normal is 6 soluble isoforms of tau. In Alzheimers pathology they become insoluble – you would get 3 bands. In pathology – the tau is phosphorylated – if dephospohorylate it then get 6 bands back.
In PSP it is a 4R disease
PiD is 3R
current classification of fronto-temporal lobe dementias
