Exam 3 Flashcards
Tau is a _ protein
microtuble associated protein
(MAP)
tau 1
Tau is a _ protein
microtuble associated protein
(MAP)
taupathies 1
Microtubles are abundant in _ but not _
neuron parts
abundant in axons & dendritic shafts but not in spines
microtubles are in dendritic _ while actin are in dendritic _
MT shafts, spines actin
Actin filaments are what structure made from what subunit?
double helizes of F actin
Microtubles subunits
alpha and beta tublin hetrodimers
Tau is a type (1 or 2) MAP
type 2
Tau also known as MAPT
taupathies 1 pg 11
in tau normal function, it
binds and stabilizes microtubules
taupathies 1
Loss of tau binding with microtubles causes _ and tau to be _
causes MT to fall apart in axon and causes tau to be sequestered in NFT
taupathies 1 pg 12
Tau domains
- 2 insets
- 4 MT binding domains
taupathies 1 pg 13
Alzheimers is a _ R tau disease
4R
frontotemporal dementia with parkinsonism (FTDP-17) isoforms differences
- one exhibits a three repeat (3R) tau isoforms with a missing exon 10
- other exhibits four repeat tau isoforms that contains exon 10
taupathies 1 pg 19
Exon 10 in protein for MAPT (tau) gene encodes
microtubule binding domain 2
Most of FTDP-17 is caused by _ mutations that cause _
3 mutations that cause problems in MT binding, aggregations and mislocalizations
taupathies 1 pg 21
the n279K mutation in FTDP-17 is a _ mutation
missense mutation
the +16 mutation does what
Increases splicing of exon 10, making the isoforms 4R more
* does this by taking out the protection that stabalizes the stem loop that causes alternative splicing of exon 10
* changes one base in the stem loop which ig destabalizes it
taupathies 1 pg 24
Cardinal features of FTDP 17
- Behavioral and personality disturbances
- cognitive deficits
- motor dysfunction
diagnosis of FTDP 17 requires
- 2/3 cardinal features
- tau mutations (genetic analyses and family history)
FTDP-17 P301L mutation causes
- tau accumulation
- drives tau to spines
the earlier hypthesis of FTDP-17 was that cell death and spine loss causes _ but then it was noticed that
earlier thought it causes memory loss but noticed that cognitive/functional deficits preceded neurodegeneration
the expression of P301L tau proteins impairs
the function of dendritic spines
taupathies 1 pg31
tau going to spines causes _ and _ but not spine loss
causes decreased NMDA-R and AMPA-R
Pick’s disease can only be diagnosed
clinically with pathology
3 main clinical presentations of FTD
- Behaviorial impairment
- Progressive nonfluent aphasia
- Semantic dementia
taupathies 2 pg 6
Tau tangles are _ tau pathologies and Pick’s bodies are _ pathologie
4R, 3R
Some functions of the frontal cortex
- working memory
- decision making
- planning
- emotions
taupathies 2 pg 7
_ is atrophied in behavioral FTD
frontal cortex
Some symptoms of behavioral FTD
- hyper activity
- hypersexuality
- impulsive
- repetitive
- poor hygiene
_ is atrophied in Progressive non fluent aphasia FTD
- broca’s area
- frontal lobe
_ is atrophied in progressive fluent aphasia FTD
- wernicke’s area
- temporal lobe
PNFA FTD core features/symptoms
- agrammatism (bad grammer)
- phonemic paraphasias (made up sounds that sound like real words but aren’t)
- anomia (difficulty finding words)
taupathies 2 pg 12
PFA FTD main features/symptoms
- progressice fluent, empty speech
- loss of word meaning, impaired naming and comprehension
- semantic paraphasias (words are spoken but mean nothing)
taupathies 2 pg 14
Drug therapies for FTD
mechanisms, not names
- cholinesterase inhibitors
- extra synaptic MNDAR atagonists
- serotonin antagonists
FTD-TDP brains contain _ inclusions
TDP-43
methods to stain pick’s bodies
- H&E staining
- Bodian’s
- AT8 Ab
- 3R tau Ab
Pick’s bodies contain _ tau
3R
Familial Pick’s disease can be caused by mutations in
R1 domains
in chronic traumatic encephalopathy, there is tau deposits in
the sulcal depth and perivascular regions
types of diffuse brain injury
- subconcussive brain trauma
- concussion
- diffuse axonal injury
- contusion
types of focal brain injuries
- hematoma
- traumatic subarachnoid hemorrhage
- penetrating trauma
clinical presentations of CTE
- behavioral and psychiatric
- cognitive
- motor
There is significant overlap between signs and symptoms of CTE and
AD and FTD
Tau pathologies in CTE are more _ than AD
more focal and superficial
_ in CTE are not as severe as Alzheimer’s
Abeta pathologies
CTE and AD are initiated at
different regions
both _ and _ tau isoforms are present in CTE but _ is more severe
both 3R and 4R isoforms are present but 4R is more severe
_ are present in _ of the _ in CTE stage 2
axonal injuries are present in the white matter ofo subcortical regions in CTE stage 2
TDP-43 and FUS inclusions are associated with
are associated with stress
initial regions of pathologies in AD and CTE
- AD: from midbrain
- CTE: cortex
signature pathologies of CTE that make it different from other diseases
Tau pathologies in the sulcal depth and perivascular regions
traditional and emerging view of CTE
- traditional: injury is a risk factor for taupathies
- emerging: TBI induced CTE shares hallmarks with other neurodegenerative disorders
TBI induces
somatodendritic accumulation of tau
The primary hallmark of ALS is the
selective killing of motor neurons
Which diseases are known to be associated with tau pathologies?
- Alzheimer’s Disease
- FTDP-17
- Pick’s Disease
There are _ tau isoforms in adult brains
10
Tau may contain either 3 or 4 microtubule binding domains due to _
alternative splicing
Which tau mutation can cause FTDP-17?
- A mutation at the first microtubule-binding domain
- A mutation at the second microtubule-binding domain
- A mutation at the Intron after Exon 10, which encodes the second microtubule-binding domain
Pick’s disease is believed to be caused by pathologies associated with Tau with
3 microtubule binding domains
Frontotemporal lobar degeneration (FTLD; also called FTD) can be caused by pathologies associated with:
- Tau
- TDP-43
What are Pick’s bodies?
Round or oval intraneuronal inclusions that contain tau
Pathologies of CTE stage 1
focal loci of tau pathologies in the cortex
CTE is often caused by
mild repeat trauma to the head
Corticospinal tracts big structure go through
Start in motor area, internal capsule, cerebral peduncles, pons and form pyramid at the bottom of brain stem
The corticospinal tract crosses or does not cross the midline
crosses the midline
symtoms of upper motor neuron ALS
- spasticity (permanant contraction of muscles)
- hyperreflexia
babinski sign
symptoms of lower motor neuron degeneration include
- muscle weakness
- muscle atrophy
- muscle cramps
- fasciculations (fine twitches of muscles)
muscle problems in ALS are due to
degeneration and death of neurons that innervate those muscles
Most common onset of ALS
spinal onset
2nd most common ALS
bulbur onset
categories of ALS are based on _
whether it effects upper or lower motor neurons and how
Neuropathology of ALS
- dying brain tissue in motor cortical neurons
- less mylenation and neurons in corticospinal tract
- TDP43 in cytoplasm of neurons
- aggregations of SOD1
- FUS aggregation
Main stats of ALS
- fatal within 1-5 years of onset
- pretty prevalant
- risk increase after 60 years old
90% of ALS is
sporadic, idopathic, late onset ALS
5-10% of ALS is
familial ALS
Familial ALS genes
- C9orf72
- SOD1
- TDP43
- FUS
sALS risk factors
- aging
- gender
- race
- cardiovascular, smoke, depression, TBI
in ALS, when motor neurons die
muscles associated weaken and paralysis happens
in the cell body, ALS can
- damage mitochondria
- cause oxidative stress
- DNA breakage
- impair DNA repair
motor neurons stop sending signals in ALS because
ALS interferes with transport mechanism of cells
ALS effects on mylein sheath because of
oligodendrocyte death
protein aggregation happens because ALS…
impairs the proteasome
mechanism of SOD1 induced toxicity
- mutant SOD1 → agregates → toxicity
- mutant SOD1 → preaggregates → directly affect toxicity
- preaggregates inhibit autophagocytosis and the proteasome (protein breakdown)
ALS lecture
pathogenic mechanism of mutant TDP43
- TDP43 has a key role in mRNA processing
- normally, stress ends and TDP43 go back to nucleus to play role^
- in ALS, stress persistance so TDP43 sequestered and turned into aggregate
- messes with alternative splicing and then there is abnormal proteins made
diagnosis of ALS requires
dysfunction of lower motor neurons and corticospinal motor neurons
ALS from upper motor neuron pathologies
primary lateral sclerosis
proped pathogenic mechanisms of TDP-43 in ALS
- Alteration of mRNA processing.
- Mislocalization and accumulation into the neuronal cytosol.
- Increased formation of protein aggregates.
- Axonal transport dysfunction.
past exam qs
When misfolded, TDP-43 forms
intranuclear and cytoplasmic inclusion bodies in neurons and glia
Direct application of mutant SOD1 protein to squid axoplasm preparations slows
anterograde transport
Pathogenic mechanism of C9ORF72 repeat expansion
- normal gene has small repeat
- mutated has G & C expansion in promotor
- causes binding of transcription factors extra
- transcription is less effective and splicing messed up
- loss of function of V1 exon
- gain of toxic function dipeptide repeat protein
ALS pg 23
mouse models of ALS make sure to have
- protein aggregation
- motor deficiets
current treatments of ALS
- sodium channel blocker
- free radical scavenger
- GABA-R positive modulator
current strategies of ALS targets:
- reducing aggregates
- cell replacement
- gene therapy
- drugs
Motor neuron disease are mainly defined by how they
destroy motor neurons
upper motor neurons direct
the lower motor neurons to produce movements
lower motor neurons control
movement in the arms, legs, chest, face, throat, toungue
MND are classified by
what motor system is effected
spinobulbar muscular atrophy (SBMA) affects
lower motor neurons
spinal muscular atrophy is a _ disease due to _
autosomal recessive disease due to mutation in SMN1
SMN1 is responsible for
survival of motor neuron, involved in spliceosome machinery
MND 2 pg 9
in SMA, _ is affected first
proximal and lower extremities muscle are affected first
MND 2 pg 9
SMA is characterized by
progressive muscle wasting and mobility impairment without sensory impariment
MND 2
SMA pathology
- glial reactivity increased
- dorsal column myelin sheath and neuronal loss
- ventral horn in spinal cord neuron loss (causes atrophy of muscles)
MND 2
dorsal column tract responsible for
touch info, feedback
* propioception
MND 2
how many subtypes of SMA and which most severe
4 subtypes, SMA 1 most severe
genetic causes of SMA
homozygous deletion or mutation of SMN1 gene
mechanism of why SMN1 mutation bad
- SMN2 undergoes alternative splicing so it creates same protein as SMN1 but without exon 7
- this same protein is non functional
- 25% of SMN2 is properly spliced so it can make up for the loss of SMN1 a little
- SMN2 protein make up in development
while healthy individuals have two copies of SMN2…
pateints with SMA can have 1-4 of them
the _ the milder SMA severity
the greater number of SMN2 copies, the milder severity
SMA1 babies have _ SMN2 copies
1 or 2
in the neuromusclular junction in SMA, see
- reduced myofiber size
- synaptic dysfunction
- impaired development
- denervation (seperation of nerve ending and muscle fibers)
in spinal cord of SMA, see
- synaptic dysfunction
- loss of motor neurons in ventral horn
- motor neuron hyperexcitability
Small nuclear ribonucleoproteins require _ and is lost in _
require SMN and is lost in SMA motor neurons
SMN is usually found in
nuclei of motor neurons
In mouse models of Spinal muscular atrophy (SMA), what are the three major
phenotypes observed?
- Selective neuronal loss in the ventral horns of the spinal cord.
- Atrophy of muscle fibers.
- Shortened lifespan.
mouse models of SMA either
- over express SMN2
- or introduce SMN2 and yeet SMN1
SMA treatment now includes
a disease modifying therapy that corrects the splicing of the SMN2 gene and make the right protein
What derivative of APP is generated from the cleavage of carboxyl-terminal fragments (CTFs) by gamma-secretase?
AICD
APP mutations linked to Alzheimer’s disease can be divided into several general classes, based on their relative locations to the Aβ sequence. How many of these classes exist?
3
PS1 and PS2 are
homologous isoforms
What apolipoprotein E allele variant is known to increasing the risk of Alzheimer’s disease?
E4
hallmark features of AD
amyloid plaques, neurofibrillary tangles and neuronal loss
What are the three genes that cause autosomal dominant forms of Alzheimer’s disease?
APP, PSEN1 and PSEN2
What is the name of the prodromal stage that precedes Alzheimer’s disease dementia?
mild cognitive impairment
What is the generic name referring to the catalytic activities that cleave the amyloid precursor protein to generate amyloid-beta peptides?
secretases
What is the generic name referring to the catalytic activities that cleave the amyloid precursor protein to generate amyloid-beta peptides?
secretases
stages of Alzheimer’s
- Normal
- Preclinical
- Mild cognitive impairment
- AD
during mild cognitive impairment stage, what part of the brain is degenerating
Entorhinal cortex
neuronal cell death starts in the _ stage of AD
mild cognitive impairment
lecture 1
what broad parts of the brain cause clinical presentation of AD
- hippocampus
- prefrontal cortex
- entorihinal cortex
2 types of cognitive tests for AD
- mini mental state exam (MMSE)
- mini cog
mini mental state examination (MMSE) is _ that indicates _
a Q&A test that is a specific indication of consiousness, speaking, memory, etc
mini cog described
- remember and repeat three names of common objects
- draw a face of the clock showing all 12 numbers and a specific time
Gross anatomical changes in Alzheimer’s
- atrophy - overall brain but effects hippocampus and EC more
- neurofibrillary tangles
- amyloid plaques
amyloid precursor protein (APP) is cleaved by _ named _, _ and _
secretases named α, β, and γ
amyloidogenic pathway
describe
- γ and β secretases cleave in two places around Aβ gene
- Aβ peptide made
- β site cleavage
non-amyloidogenic pathway
describe and why does it exist
- α cleaves in the middle Aβ peptide
- protective pathway to decrease probability of plaques being makes
- no Aβ peptide made
- α site cleavage
pathway in cell of APP
- APP secreted to cell surface from golgi
- goes to sorting endosome if beta cleaved
the tay gene undergoes _ and has _ isoforms
alternative splicing, has 6 isoforms
tau normally
stabalizes and binds microtubles
_ of tau causes it to not _ and instead form _
phsophorylation of tau makes it not bind to MT and instead form NFT
clinical hallmark of ALS
- upper AND lower motor neuron symptoms
Tau NFTs affect the _ first then
affects entorhinal cortex and locus coerulus first then propogates upward into basal forebrain
in AD, there is monoaminergic deficits in _ neurons that regulate
acetylecholine neurons that regulate mood, working memory, reward, associative learning
progression in Braak staging of tau
- start in EC
- spread to limbic areas (stage 3ish)
- spread to neocortical areas
familial AD is broadly caused by
mutations in APP
PSEN1 is
active catalytic site of gamma secretase
can be mutated in AD
PEN2 and APH-1 are
modulators of gamma secretase
NCT helps with
gamma secretase recognition of substrates
early onset familial AD mutations are in
APP and PSEN-1
late familial ADD onset mutation in
PSEN-2
PS1-E280A mutation is
a mutation in a specfic gene pool in colombia that causes AD
genetic risk factor for sporatic AD is mostly
APOE gene polymorphism
sporadic AD risk factors
- aging
- genetics (APOE)
- gender
- excersise (reduce risk)
- TBI
_ is the non modifiable risk factor in sporadic AD
age
having more copies of _ increases risk of sporadic AD
APOE4
APOE is on chromosome _ and encodes _ alleles
chromosome 19, 3 alleles
APOE has domains for
receptor binding and lipid binding
what APOEallele reduces and raises risk of AD
- ApoE2 reduces risk
- ApoE3 neutral
- ApoE4 increases risk
Two of the most consistent pathological findings in EARLY stage Chronic
Traumatic Encephalopathy (CTE) are
focal deposits of phosphorylated tau and focal axonal varicosities in the cortex.
Which genes linked to familial Amyotrophic Lateral Sclerosis (fALS) interfere with normal proteasomal or autophagic degradation?
- SOD1
- UBQLN2
- TDP43
- VCP
In which cellular compartment does the Ɣ-secretase complex generate amyloid-β peptides from carboxyterminal fragments of APP?
late endosome/multivesicular body
What are the major components of the Ɣ-secretase complex?
- PSEN-1
- PEN-2
- NCT
- APH-1
APP overexpressing transgenic mice key features
Has:
* amyloid plaques
* selective neuronal loss
* cognitive decline
does not have tau mutations or atrophy
limitations of APP & hTau over expressing mice
APP do not express tau mutations but when express tau find out that tau doesn’t cause AD so
APP/MAPT knock in mice features and limitations
- amyloid deposits shown
- tau phosphorylation
Limitations: - neuronal loss
- no NFT
- may or may not have memory deficits
Amyloid plaques visualized by and shows
PiB:
* binds to plaques
* increased in frontal cortex and preculneus
FDG-PET:
* shows glucose utilization
* decrease glucose utilization in AD
in AD, amyloid plaques increase in the
prefrontal cortex and preculneus
structural brain changes with Alzeimer’s
hippocampus volume goes down
a petient can have _ but still not have AD
amyloid plaques
IN AD, _ level of A-beta _ is
CSF levels of a beta 42 is decreased 50%
in CSF, _ used to diagnose AD
Abeta 42:40 ratio
why is Abeta42 reduced in CSF of AD
plaques stay in brain so not filtering out in CSF
in CSF, _ increased in AD
total tau increased 300%
why does CSF higher t-tau in AD
because tau is phosphorylated and realeased from MT so it comes out in CSF
CSF t tau shows _ while p tau shows _
ta tau shows intensity of neuroaxonal degeneration
pptau shows tangle pathology
1st biomarker of AD that shows up is
amyloid plaques
blood based test for AD shows
chance of having AD
cholinesterase inhibitors _ and they are a _ treatment
inhibit breakdown of AceCh and are a symptomatic treatment
tau path in AD brain
phosphorylates, moves to axon to cell body (from dendrite spines), make NFT and kill neuron, bad tau spread and yeet healthy tau, pattern spreading matching symptoms
_ mediates _ in AD
tau mediates Abeta induced deficits
how do they know tau mediates abeta
when removed tau gene in AD mice, cognitive function improved
familial AD vs sporadic when it comes to Abeta
- familial: problems with abeta production (increase in abeta 42)
- sporadic: failure of abeta clearance, increasing levels
Abeta oligomers are
synaptic toxins
proposed role of APOE in AD
- tau mediated neurodegen (up)
- neuronal toxicity (up)
- Abeta clearance (down)
- more a beta aggregation
- down insulin signaling
