Exam 3 Flashcards
1
Q
Tau is a _ protein
A
microtuble associated protein
(MAP)
tau 1
2
Q
Tau is a _ protein
A
microtuble associated protein
(MAP)
taupathies 1
3
Q
Microtubles are abundant in _ but not _
neuron parts
A
abundant in axons & dendritic shafts but not in spines
4
Q
microtubles are in dendritic _ while actin are in dendritic _
A
MT shafts, spines actin
5
Q
Actin filaments are what structure made from what subunit?
A
double helizes of F actin
6
Q
Microtubles subunits
A
alpha and beta tublin hetrodimers
7
Q
Tau is a type (1 or 2) MAP
A
type 2
Tau also known as MAPT
taupathies 1 pg 11
8
Q
in tau normal function, it
A
binds and stabilizes microtubules
taupathies 1
9
Q
Loss of tau binding with microtubles causes _ and tau to be _
A
causes MT to fall apart in axon and causes tau to be sequestered in NFT
taupathies 1 pg 12
10
Q
Tau domains
A
- 2 insets
- 4 MT binding domains
taupathies 1 pg 13
11
Q
Alzheimers is a _ R tau disease
A
4R
12
Q
frontotemporal dementia with parkinsonism (FTDP-17) isoforms differences
A
- 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
13
Q
Exon 10 in protein for MAPT (tau) gene encodes
A
microtubule binding domain 2
14
Q
Most of FTDP-17 is caused by _ mutations that cause _
A
3 mutations that cause problems in MT binding, aggregations and mislocalizations
taupathies 1 pg 21
15
Q
the n279K mutation in FTDP-17 is a _ mutation
A
missense mutation
16
Q
the +16 mutation does what
A
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
17
Q
Cardinal features of FTDP 17
A
- Behavioral and personality disturbances
- cognitive deficits
- motor dysfunction
18
Q
diagnosis of FTDP 17 requires
A
- 2/3 cardinal features
- tau mutations (genetic analyses and family history)
19
Q
FTDP-17 P301L mutation causes
A
- tau accumulation
- drives tau to spines
20
Q
the earlier hypthesis of FTDP-17 was that cell death and spine loss causes _ but then it was noticed that
A
earlier thought it causes memory loss but noticed that cognitive/functional deficits preceded neurodegeneration
21
Q
the expression of P301L tau proteins impairs
A
the function of dendritic spines
taupathies 1 pg31
22
Q
tau going to spines causes _ and _ but not spine loss
A
causes decreased NMDA-R and AMPA-R
23
Q
Pick’s disease can only be diagnosed
A
clinically with pathology
24
Q
3 main clinical presentations of FTD
A
- Behaviorial impairment
- Progressive nonfluent aphasia
- Semantic dementia
taupathies 2 pg 6
25
Tau tangles are _ tau pathologies and Pick’s bodies are _ pathologie
4R, 3R
26
Some functions of the frontal cortex
* working memory
* decision making
* planning
* emotions
## Footnote
taupathies 2 pg 7
27
_ is atrophied in behavioral FTD
frontal cortex
28
Some symptoms of behavioral FTD
* hyper activity
* hypersexuality
* impulsive
* repetitive
* poor hygiene
29
_ is atrophied in Progressive non fluent aphasia FTD
* broca's area
* frontal lobe
30
_ is atrophied in progressive fluent aphasia FTD
* wernicke's area
* temporal lobe
31
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)*
## Footnote
taupathies 2 pg 12
32
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)*
## Footnote
taupathies 2 pg 14
33
Drug therapies for FTD
| mechanisms, not names
1. cholinesterase inhibitors
2. extra synaptic MNDAR atagonists
3. serotonin antagonists
34
FTD-TDP brains contain _ inclusions
TDP-43
35
methods to stain pick's bodies
* H&E staining
* Bodian's
* AT8 Ab
* 3R tau Ab
36
Pick's bodies contain _ tau
3R
37
Familial Pick's disease can be caused by mutations in
R1 domains
38
in chronic traumatic encephalopathy, there is tau deposits in
the sulcal depth and perivascular regions
39
types of diffuse brain injury
* subconcussive brain trauma
* concussion
* diffuse axonal injury
* contusion
40
types of focal brain injuries
* hematoma
* traumatic subarachnoid hemorrhage
* penetrating trauma
41
clinical presentations of CTE
* behavioral and psychiatric
* cognitive
* motor
42
There is significant overlap between signs and symptoms of CTE and
AD and FTD
43
Tau pathologies in CTE are more _ than AD
more focal and superficial
44
_ in CTE are not as severe as Alzheimer's
Abeta pathologies
45
CTE and AD are initiated at
different regions
46
both _ and _ tau isoforms are present in CTE but _ is more severe
both 3R and 4R isoforms are present but 4R is more severe
47
_ are present in _ of the _ in CTE stage 2
axonal injuries are present in the white matter ofo subcortical regions in CTE stage 2
48
TDP-43 and FUS inclusions are associated with
are associated with stress
49
initial regions of pathologies in AD and CTE
* AD: from midbrain
* CTE: cortex
50
signature pathologies of CTE that make it different from other diseases
Tau pathologies in the sulcal depth and perivascular regions
51
traditional and emerging view of CTE
* **traditional**: injury is a risk factor for taupathies
* **emerging**: TBI induced CTE shares hallmarks with other neurodegenerative disorders
52
TBI induces
somatodendritic accumulation of tau
53
The primary hallmark of ALS is the
selective killing of motor neurons
54
Which diseases are known to be associated with tau pathologies?
* Alzheimer's Disease
* FTDP-17
* Pick's Disease
55
There are _ tau isoforms in adult brains
10
56
Tau may contain either 3 or 4 microtubule binding domains due to _
alternative splicing
57
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
58
Pick's disease is believed to be caused by pathologies associated with Tau with
3 microtubule binding domains
59
Frontotemporal lobar degeneration (FTLD; also called FTD) can be caused by pathologies associated with:
* Tau
* TDP-43
60
What are Pick's bodies?
Round or oval intraneuronal inclusions that contain tau
61
Pathologies of CTE stage 1
focal loci of tau pathologies in the cortex
62
CTE is often caused by
mild repeat trauma to the head
63
Corticospinal tracts big structure go through
Start in motor area, internal capsule, cerebral peduncles, pons and form pyramid at the bottom of brain stem
64
The corticospinal tract crosses or does not cross the midline
crosses the midline
65
symtoms of upper motor neuron ALS
* spasticity *(permanant contraction of muscles)*
* hyperreflexia
| babinski sign
66
symptoms of lower motor neuron degeneration include
* muscle weakness
* muscle atrophy
* muscle cramps
* fasciculations *(fine twitches of muscles)*
67
muscle problems in ALS are due to
degeneration and death of neurons that innervate those muscles
68
Most common onset of ALS
spinal onset
69
2nd most common ALS
bulbur onset
70
categories of ALS are based on _
whether it effects upper or lower motor neurons and how
71
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
72
Main stats of ALS
* fatal within 1-5 years of onset
* pretty prevalant
* risk increase after 60 years old
73
90% of ALS is
sporadic, idopathic, late onset ALS
74
5-10% of ALS is
familial ALS
75
Familial ALS genes
* C9orf72
* SOD1
* TDP43
* FUS
76
sALS risk factors
* aging
* gender
* race
* cardiovascular, smoke, depression, TBI
77
in ALS, when motor neurons die
muscles associated weaken and paralysis happens
78
in the cell body, ALS can
* damage mitochondria
* cause oxidative stress
* DNA breakage
* impair DNA repair
79
motor neurons stop sending signals in ALS because
ALS interferes with transport mechanism of cells
80
ALS effects on mylein sheath because of
oligodendrocyte death
81
protein aggregation happens because ALS...
impairs the proteasome
82
mechanism of SOD1 induced toxicity
* mutant SOD1 → agregates → toxicity
* mutant SOD1 → preaggregates → directly affect toxicity
* preaggregates inhibit autophagocytosis and the proteasome (protein breakdown)
## Footnote
ALS lecture
83
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
84
diagnosis of ALS requires
dysfunction of lower motor neurons and corticospinal motor neurons
85
ALS from upper motor neuron pathologies
primary lateral sclerosis
86
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.
## Footnote
past exam qs
87
When misfolded, TDP-43 forms
intranuclear and cytoplasmic inclusion bodies in neurons and glia
88
Direct application of mutant SOD1 protein to squid axoplasm preparations slows
anterograde transport
89
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**
## Footnote
ALS pg 23
90
mouse models of ALS make sure to have
* protein aggregation
* motor deficiets
91
current treatments of ALS
* sodium channel blocker
* free radical scavenger
* GABA-R positive modulator
92
current strategies of ALS targets:
* reducing aggregates
* cell replacement
* gene therapy
* drugs
93
Motor neuron disease are mainly defined by how they
destroy motor neurons
94
upper motor neurons direct
the lower motor neurons to produce movements
95
lower motor neurons control
movement in the arms, legs, chest, face, throat, toungue
96
MND are classified by
what motor system is effected
97
spinobulbar muscular atrophy (SBMA) affects
lower motor neurons
98
spinal muscular atrophy is a _ disease due to _
autosomal recessive disease due to mutation in SMN1
99
SMN1 is responsible for
survival of motor neuron, involved in spliceosome machinery
## Footnote
MND 2 pg 9
100
in SMA, _ is affected first
proximal and lower extremities muscle are affected first
## Footnote
MND 2 pg 9
101
SMA is characterized by
progressive muscle wasting and mobility impairment without sensory impariment
## Footnote
MND 2
102
SMA pathology
* glial reactivity increased
* dorsal column myelin sheath and neuronal loss
* ventral horn in spinal cord neuron loss *(causes atrophy of muscles)*
## Footnote
MND 2
103
dorsal column tract responsible for
touch info, feedback
* propioception
## Footnote
MND 2
104
how many subtypes of SMA and which most severe
4 subtypes, SMA 1 most severe
105
genetic causes of SMA
homozygous deletion or mutation of SMN1 gene
106
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
107
while healthy individuals have two copies of SMN2...
pateints with SMA can have 1-4 of them
108
the _ the milder SMA severity
the greater number of SMN2 copies, the milder severity
109
SMA1 babies have _ SMN2 copies
1 or 2
110
in the neuromusclular junction in SMA, see
* reduced myofiber size
* synaptic dysfunction
* impaired development
* denervation (seperation of nerve ending and muscle fibers)
111
in spinal cord of SMA, see
* synaptic dysfunction
* loss of motor neurons in ventral horn
* motor neuron hyperexcitability
112
Small nuclear ribonucleoproteins require _ and is lost in _
require SMN and is lost in SMA motor neurons
113
SMN is usually found in
nuclei of motor neurons
114
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.
115
mouse models of SMA either
* over express SMN2
* or introduce SMN2 and yeet SMN1
116
SMA treatment now includes
a disease modifying therapy that corrects the splicing of the SMN2 gene and make the right protein
117
What derivative of APP is generated from the cleavage of carboxyl-terminal fragments (CTFs) by gamma-secretase?
AICD
118
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
119
PS1 and PS2 are
homologous isoforms
120
What apolipoprotein E allele variant is known to increasing the risk of Alzheimer’s disease?
E4
121
hallmark features of AD
amyloid plaques, neurofibrillary tangles and neuronal loss
122
What are the three genes that cause autosomal dominant forms of Alzheimer’s disease?
APP, PSEN1 and PSEN2
123
What is the name of the prodromal stage that precedes Alzheimer’s disease dementia?
mild cognitive impairment
124
What is the generic name referring to the catalytic activities that cleave the amyloid precursor protein to generate amyloid-beta peptides?
secretases
125
What is the generic name referring to the catalytic activities that cleave the amyloid precursor protein to generate amyloid-beta peptides?
secretases
126
stages of Alzheimer's
1. Normal
2. Preclinical
3. Mild cognitive impairment
4. AD
127
during mild cognitive impairment stage, what part of the brain is degenerating
Entorhinal cortex
128
neuronal cell death starts in the _ stage of AD
mild cognitive impairment
## Footnote
lecture 1
129
what broad parts of the brain cause clinical presentation of AD
* hippocampus
* prefrontal cortex
* entorihinal cortex
130
2 types of cognitive tests for AD
* mini mental state exam (MMSE)
* mini cog
131
mini mental state examination (MMSE) is _ that indicates _
a Q&A test that is a specific indication of consiousness, speaking, memory, etc
132
mini cog described
1. remember and repeat three names of common objects
2. draw a face of the clock showing all 12 numbers and a specific time
133
Gross anatomical changes in Alzheimer's
* atrophy - overall brain but effects hippocampus and EC more
* neurofibrillary tangles
* amyloid plaques
134
amyloid precursor protein (APP) is cleaved by _ named _, _ and _
secretases named α, β, and γ
135
amyloidogenic pathway
| describe
* γ and β secretases cleave in two places around Aβ gene
* Aβ peptide made
* β site cleavage
136
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
137
pathway in cell of APP
* APP secreted to cell surface from golgi
* goes to sorting endosome if beta cleaved
138
the tay gene undergoes _ and has _ isoforms
alternative splicing, has 6 isoforms
139
tau normally
stabalizes and binds microtubles
140
_ of tau causes it to not _ and instead form _
phsophorylation of tau makes it not bind to MT and instead form NFT
141
clinical hallmark of ALS
* upper AND lower motor neuron symptoms
142
Tau NFTs affect the _ first then
affects entorhinal cortex and locus coerulus first then propogates upward into basal forebrain
143
in AD, there is monoaminergic deficits in _ neurons that regulate
acetylecholine neurons that regulate mood, working memory, reward, associative learning
144
progression in Braak staging of tau
* start in EC
* spread to limbic areas (stage 3ish)
* spread to neocortical areas
145
familial AD is broadly caused by
mutations in APP
146
PSEN1 is
active catalytic site of gamma secretase
| can be mutated in AD
147
PEN2 and APH-1 are
modulators of gamma secretase
148
NCT helps with
gamma secretase recognition of substrates
149
early onset familial AD mutations are in
APP and PSEN-1
150
late familial ADD onset mutation in
PSEN-2
151
PS1-E280A mutation is
a mutation in a specfic gene pool in colombia that causes AD
152
genetic risk factor for sporatic AD is mostly
APOE gene polymorphism
153
sporadic AD risk factors
* aging
* genetics (*APOE*)
* gender
* excersise (*reduce risk*)
* TBI
154
_ is the non modifiable risk factor in sporadic AD
age
155
having more copies of _ increases risk of sporadic AD
APOE4
156
APOE is on chromosome _ and encodes _ alleles
chromosome 19, 3 alleles
157
APOE has domains for
receptor binding and lipid binding
158
what APOEallele reduces and raises risk of AD
* ApoE2 reduces risk
* ApoE3 neutral
* ApoE4 increases risk
159
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.
160
Which genes linked to familial Amyotrophic Lateral Sclerosis (fALS) interfere with normal proteasomal or autophagic degradation?
* SOD1
* UBQLN2
* TDP43
* VCP
161
In which cellular compartment does the Ɣ-secretase complex generate amyloid-β peptides from carboxyterminal fragments of APP?
late endosome/multivesicular body
162
What are the major components of the Ɣ-secretase complex?
* PSEN-1
* PEN-2
* NCT
* APH-1
163
APP overexpressing transgenic mice key features
Has:
* amyloid plaques
* selective neuronal loss
* cognitive decline
| does not have tau mutations or atrophy
164
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
165
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
166
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
167
in AD, amyloid plaques increase in the
prefrontal cortex and preculneus
168
structural brain changes with Alzeimer's
hippocampus volume goes down
169
a petient can have _ but still not have AD
amyloid plaques
170
IN AD, _ level of A-beta _ is
CSF levels of a beta 42 is decreased 50%
171
in CSF, _ used to diagnose AD
Abeta 42:40 ratio
172
why is Abeta42 reduced in CSF of AD
plaques stay in brain so not filtering out in CSF
173
in CSF, _ increased in AD
total tau increased 300%
174
why does CSF higher t-tau in AD
because tau is phosphorylated and realeased from MT so it comes out in CSF
175
CSF t tau shows _ while p tau shows _
ta tau shows intensity of neuroaxonal degeneration
pptau shows tangle pathology
176
1st biomarker of AD that shows up is
amyloid plaques
177
blood based test for AD shows
chance of having AD
178
cholinesterase inhibitors _ and they are a _ treatment
inhibit breakdown of AceCh and are a symptomatic treatment
179
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
180
_ mediates _ in AD
tau mediates Abeta induced deficits
181
how do they know tau mediates abeta
when removed tau gene in AD mice, cognitive function improved
182
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
183
Abeta oligomers are
synaptic toxins
184
proposed role of APOE in AD
* tau mediated neurodegen (up)
* neuronal toxicity (up)
* Abeta clearance (down)
* more a beta aggregation
* down insulin signaling
