neurodegenerative disease Flashcards
What are the consequences of failure of FAT?
accumulation of waste in axonal terminals
loss of replenishing substrates
= loss of synaptic connections = apoptosis
What are two contributing factors in the mechanism of Alzheimer’s disease?
- Protein misfolding/buildup (infection, diabetes, genes)
- Diminished cerebral arteriolar compliance (DM, HTN, Age)
=iminished interstitial clearance of ppt’d misfolded protein + (AB amyloid clogged ISF pathways)
= Accumulation of hyperphosphorylated TAU and AB Amyloid
How do Tau and B amyloid spread through the brain?
Tau - Neurofibrillary tangle, spreads up the brainstem to the cortex
B amyloid plaque - starts from frontal lobe and spreads backwards
What are the two pathologic precipitated proteins in Alzheimer disease? what does this combination cause?
B-amyloid plaques in interstitial fluid channels hyperphosphorylated Tau (tangles)
causes LOSS of NMDA receptors + disrupt FAT mechanism
How does Alzheimers cause memory loss
Soluble B amyloid binds to PrPc (Prion protein) mediated by Fyn kinase (Toxic to AMPA receptors) = requiried for short and long term memory formation)
What are 3 inherited Alzheimer Factors?
- APOE 4 - disrupted lipid/cholesterol trafficking
- Presenilin protein (PS1 and PS2) = MOST COMMON
- Missense mutations of APP (chromosome 21)
What is the initial cerebral geographic presentation of Alzheimers?
Basal frontal, basal temporal - spreads to remaining cortex
What is the clinical presentation of Alzheimers?
loss of short term memory
loss of judgement
What aberrant protein is a/w parkinson disease?
alpha-synuclein
What gene encodes TAU?
MAPT
What are 3 types of Tauopathies? Where in the brain do each affect?
- Frontal Temporal Dementia (FTP) - Picks
- -frontal cortex, ant temp cortex, basal ganglia
- -young people - Progressive supranuclear palsy (PSP)
- -subcortical gray matter, brainstem, cerebral cortex
- -difficult fine motor control, probs looking down, balance - Chronic traumatic encephalopathy (CTE) - diffuse cortical and subcortical involvement
What two genes are present in half of FTD’s?
Tau
TDP43
behavioral change (apathy, disinhibition, agitation), lack of insight, blunted emotions > cognitive deficits, alien hand, apraxia, myoclonus, limb rigidity
Frontal temporal dementia
supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia, and dementia
Progressive supranuclear palsy
dementia Parkinson’s like features of rigidity, tremor, bradykinesia
Chronic Traumatic encephalopathy
a-synuclein disease
diffuse cortical neuron involvement
Lewy body dementia
a-synuclein disease
Lewy body accumulation primarily in the oligodendrocytes
MSA (multisystems Atrophy)
How are lewy bodies formed?
Dopamine binds to asynuclein and form protofibrils which aggregate
What is the function of a-synuclein? what condition causes it to build up?
attenuates neurotransmission
Familial parkinsons - LRRK2 mutation - buildup
- Preceded by REM sleep behavior disorder by 1-2 decades
2. Combination of parkinsonian features, dementia and autonomic insufficiency (prominent orthostatic hypotension)
Multisystem atrophy (MSA) --synuclein accumulates in Oligodendrocytes
What are two molecular players in Huntington Disease?
- Huntington protein (HTT) - fast axonal transport protein
2. Autosomal dominant disease chromosome 4p 16.3
What regions of the brain does Huntington Disease affect?
Caudate, putament, cerebral cortex
HTT protein
chorea
dementia
behavioral changes
Huntington Disease
