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NSCI 4501 > Exam 3 > Flashcards

Exam 3 Flashcards

1
Q

Tau is a _ protein

A

microtuble associated protein

(MAP)

tau 1

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2
Q

Tau is a _ protein

A

microtuble associated protein

(MAP)

taupathies 1

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3
Q

Microtubles are abundant in _ but not _

neuron parts

A

abundant in axons & dendritic shafts but not in spines

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4
Q

microtubles are in dendritic _ while actin are in dendritic _

A

MT shafts, spines actin

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5
Q

Actin filaments are what structure made from what subunit?

A

double helizes of F actin

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6
Q

Microtubles subunits

A

alpha and beta tublin hetrodimers

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7
Q

Tau is a type (1 or 2) MAP

A

type 2

Tau also known as MAPT

taupathies 1 pg 11

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8
Q

in tau normal function, it

A

binds and stabilizes microtubules

taupathies 1

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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

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10
Q

Tau domains

A
  • 2 insets
  • 4 MT binding domains

taupathies 1 pg 13

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11
Q

Alzheimers is a _ R tau disease

A

4R

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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

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13
Q

Exon 10 in protein for MAPT (tau) gene encodes

A

microtubule binding domain 2

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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

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15
Q

the n279K mutation in FTDP-17 is a _ mutation

A

missense mutation

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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

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17
Q

Cardinal features of FTDP 17

A
  • Behavioral and personality disturbances
  • cognitive deficits
  • motor dysfunction
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18
Q

diagnosis of FTDP 17 requires

A
  • 2/3 cardinal features
  • tau mutations (genetic analyses and family history)
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19
Q

FTDP-17 P301L mutation causes

A
  • tau accumulation
  • drives tau to spines
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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

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21
Q

the expression of P301L tau proteins impairs

A

the function of dendritic spines

taupathies 1 pg31

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22
Q

tau going to spines causes _ and _ but not spine loss

A

causes decreased NMDA-R and AMPA-R

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23
Q

Pick’s disease can only be diagnosed

A

clinically with pathology

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24
Q

3 main clinical presentations of FTD

A
  1. Behaviorial impairment
  2. Progressive nonfluent aphasia
  3. Semantic dementia

taupathies 2 pg 6

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25
Q

Tau tangles are _ tau pathologies and Pick’s bodies are _ pathologie

A

4R, 3R

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26
Q

Some functions of the frontal cortex

A
  • working memory
  • decision making
  • planning
  • emotions

taupathies 2 pg 7

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27
Q

_ is atrophied in behavioral FTD

A

frontal cortex

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28
Q

Some symptoms of behavioral FTD

A
  • hyper activity
  • hypersexuality
  • impulsive
  • repetitive
  • poor hygiene
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29
Q

_ is atrophied in Progressive non fluent aphasia FTD

A
  • broca’s area
  • frontal lobe
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30
Q

_ is atrophied in progressive fluent aphasia FTD

A
  • wernicke’s area
  • temporal lobe
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31
Q

PNFA FTD core features/symptoms

A
  • agrammatism (bad grammer)
  • phonemic paraphasias (made up sounds that sound like real words but aren’t)
  • anomia (difficulty finding words)

taupathies 2 pg 12

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32
Q

PFA FTD main features/symptoms

A
  • progressice fluent, empty speech
  • loss of word meaning, impaired naming and comprehension
  • semantic paraphasias (words are spoken but mean nothing)

taupathies 2 pg 14

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33
Q

Drug therapies for FTD

mechanisms, not names

A
  1. cholinesterase inhibitors
  2. extra synaptic MNDAR atagonists
  3. serotonin antagonists
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34
Q

FTD-TDP brains contain _ inclusions

A

TDP-43

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35
Q

methods to stain pick’s bodies

A
  • H&E staining
  • Bodian’s
  • AT8 Ab
  • 3R tau Ab
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36
Q

Pick’s bodies contain _ tau

A

3R

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37
Q

Familial Pick’s disease can be caused by mutations in

A

R1 domains

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38
Q

in chronic traumatic encephalopathy, there is tau deposits in

A

the sulcal depth and perivascular regions

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39
Q

types of diffuse brain injury

A
  • subconcussive brain trauma
  • concussion
  • diffuse axonal injury
  • contusion
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40
Q

types of focal brain injuries

A
  • hematoma
  • traumatic subarachnoid hemorrhage
  • penetrating trauma
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41
Q

clinical presentations of CTE

A
  • behavioral and psychiatric
  • cognitive
  • motor
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42
Q

There is significant overlap between signs and symptoms of CTE and

A

AD and FTD

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43
Q

Tau pathologies in CTE are more _ than AD

A

more focal and superficial

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44
Q

_ in CTE are not as severe as Alzheimer’s

A

Abeta pathologies

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45
Q

CTE and AD are initiated at

A

different regions

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46
Q

both _ and _ tau isoforms are present in CTE but _ is more severe

A

both 3R and 4R isoforms are present but 4R is more severe

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47
Q

_ are present in _ of the _ in CTE stage 2

A

axonal injuries are present in the white matter ofo subcortical regions in CTE stage 2

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48
Q

TDP-43 and FUS inclusions are associated with

A

are associated with stress

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49
Q

initial regions of pathologies in AD and CTE

A
  • AD: from midbrain
  • CTE: cortex
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50
Q

signature pathologies of CTE that make it different from other diseases

A

Tau pathologies in the sulcal depth and perivascular regions

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51
Q

traditional and emerging view of CTE

A
  • traditional: injury is a risk factor for taupathies
  • emerging: TBI induced CTE shares hallmarks with other neurodegenerative disorders
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52
Q

TBI induces

A

somatodendritic accumulation of tau

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53
Q

The primary hallmark of ALS is the

A

selective killing of motor neurons

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54
Q

Which diseases are known to be associated with tau pathologies?

A
  • Alzheimer’s Disease
  • FTDP-17
  • Pick’s Disease
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55
Q

There are _ tau isoforms in adult brains

A

10

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56
Q

Tau may contain either 3 or 4 microtubule binding domains due to _

A

alternative splicing

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57
Q

Which tau mutation can cause FTDP-17?

A
  • 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
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58
Q

Pick’s disease is believed to be caused by pathologies associated with Tau with

A

3 microtubule binding domains

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59
Q

Frontotemporal lobar degeneration (FTLD; also called FTD) can be caused by pathologies associated with:

A
  • Tau
  • TDP-43
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60
Q

What are Pick’s bodies?

A

Round or oval intraneuronal inclusions that contain tau

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61
Q

Pathologies of CTE stage 1

A

focal loci of tau pathologies in the cortex

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62
Q

CTE is often caused by

A

mild repeat trauma to the head

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63
Q

Corticospinal tracts big structure go through

A

Start in motor area, internal capsule, cerebral peduncles, pons and form pyramid at the bottom of brain stem

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64
Q

The corticospinal tract crosses or does not cross the midline

A

crosses the midline

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65
Q

symtoms of upper motor neuron ALS

A
  • spasticity (permanant contraction of muscles)
  • hyperreflexia

babinski sign

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66
Q

symptoms of lower motor neuron degeneration include

A
  • muscle weakness
  • muscle atrophy
  • muscle cramps
  • fasciculations (fine twitches of muscles)
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67
Q

muscle problems in ALS are due to

A

degeneration and death of neurons that innervate those muscles

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68
Q

Most common onset of ALS

A

spinal onset

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69
Q

2nd most common ALS

A

bulbur onset

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70
Q

categories of ALS are based on _

A

whether it effects upper or lower motor neurons and how

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71
Q

Neuropathology of ALS

A
  • dying brain tissue in motor cortical neurons
  • less mylenation and neurons in corticospinal tract
  • TDP43 in cytoplasm of neurons
  • aggregations of SOD1
  • FUS aggregation
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72
Q

Main stats of ALS

A
  • fatal within 1-5 years of onset
  • pretty prevalant
  • risk increase after 60 years old
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73
Q

90% of ALS is

A

sporadic, idopathic, late onset ALS

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74
Q

5-10% of ALS is

A

familial ALS

75
Q

Familial ALS genes

A
  • C9orf72
  • SOD1
  • TDP43
  • FUS
76
Q

sALS risk factors

A
  • aging
  • gender
  • race
  • cardiovascular, smoke, depression, TBI
77
Q

in ALS, when motor neurons die

A

muscles associated weaken and paralysis happens

78
Q

in the cell body, ALS can

A
  • damage mitochondria
  • cause oxidative stress
  • DNA breakage
  • impair DNA repair
79
Q

motor neurons stop sending signals in ALS because

A

ALS interferes with transport mechanism of cells

80
Q

ALS effects on mylein sheath because of

A

oligodendrocyte death

81
Q

protein aggregation happens because ALS…

A

impairs the proteasome

82
Q

mechanism of SOD1 induced toxicity

A
  • mutant SOD1 → agregates → toxicity
  • mutant SOD1 → preaggregates → directly affect toxicity
  • preaggregates inhibit autophagocytosis and the proteasome (protein breakdown)

ALS lecture

83
Q

pathogenic mechanism of mutant TDP43

A
  • 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
Q

diagnosis of ALS requires

A

dysfunction of lower motor neurons and corticospinal motor neurons

85
Q

ALS from upper motor neuron pathologies

A

primary lateral sclerosis

86
Q

proped pathogenic mechanisms of TDP-43 in ALS

A
  • Alteration of mRNA processing.
  • Mislocalization and accumulation into the neuronal cytosol.
  • Increased formation of protein aggregates.
  • Axonal transport dysfunction.

past exam qs

87
Q

When misfolded, TDP-43 forms

A

intranuclear and cytoplasmic inclusion bodies in neurons and glia

88
Q

Direct application of mutant SOD1 protein to squid axoplasm preparations slows

A

anterograde transport

89
Q

Pathogenic mechanism of C9ORF72 repeat expansion

A
  • 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

90
Q

mouse models of ALS make sure to have

A
  • protein aggregation
  • motor deficiets
91
Q

current treatments of ALS

A
  • sodium channel blocker
  • free radical scavenger
  • GABA-R positive modulator
92
Q

current strategies of ALS targets:

A
  • reducing aggregates
  • cell replacement
  • gene therapy
  • drugs
93
Q

Motor neuron disease are mainly defined by how they

A

destroy motor neurons

94
Q

upper motor neurons direct

A

the lower motor neurons to produce movements

95
Q

lower motor neurons control

A

movement in the arms, legs, chest, face, throat, toungue

96
Q

MND are classified by

A

what motor system is effected

97
Q

spinobulbar muscular atrophy (SBMA) affects

A

lower motor neurons

98
Q

spinal muscular atrophy is a _ disease due to _

A

autosomal recessive disease due to mutation in SMN1

99
Q

SMN1 is responsible for

A

survival of motor neuron, involved in spliceosome machinery

MND 2 pg 9

100
Q

in SMA, _ is affected first

A

proximal and lower extremities muscle are affected first

MND 2 pg 9

101
Q

SMA is characterized by

A

progressive muscle wasting and mobility impairment without sensory impariment

MND 2

102
Q

SMA pathology

A
  • glial reactivity increased
  • dorsal column myelin sheath and neuronal loss
  • ventral horn in spinal cord neuron loss (causes atrophy of muscles)

MND 2

103
Q

dorsal column tract responsible for

A

touch info, feedback
* propioception

MND 2

104
Q

how many subtypes of SMA and which most severe

A

4 subtypes, SMA 1 most severe

105
Q

genetic causes of SMA

A

homozygous deletion or mutation of SMN1 gene

106
Q

mechanism of why SMN1 mutation bad

A
  • 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
Q

while healthy individuals have two copies of SMN2…

A

pateints with SMA can have 1-4 of them

108
Q

the _ the milder SMA severity

A

the greater number of SMN2 copies, the milder severity

109
Q

SMA1 babies have _ SMN2 copies

A

1 or 2

110
Q

in the neuromusclular junction in SMA, see

A
  • reduced myofiber size
  • synaptic dysfunction
  • impaired development
  • denervation (seperation of nerve ending and muscle fibers)
111
Q

in spinal cord of SMA, see

A
  • synaptic dysfunction
  • loss of motor neurons in ventral horn
  • motor neuron hyperexcitability
112
Q

Small nuclear ribonucleoproteins require _ and is lost in _

A

require SMN and is lost in SMA motor neurons

113
Q

SMN is usually found in

A

nuclei of motor neurons

114
Q

In mouse models of Spinal muscular atrophy (SMA), what are the three major
phenotypes observed?

A
  • Selective neuronal loss in the ventral horns of the spinal cord.
  • Atrophy of muscle fibers.
  • Shortened lifespan.
115
Q

mouse models of SMA either

A
  • over express SMN2
  • or introduce SMN2 and yeet SMN1
116
Q

SMA treatment now includes

A

a disease modifying therapy that corrects the splicing of the SMN2 gene and make the right protein

117
Q

What derivative of APP is generated from the cleavage of carboxyl-terminal fragments (CTFs) by gamma-secretase?

A

AICD

118
Q

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?

A

3

119
Q

PS1 and PS2 are

A

homologous isoforms

120
Q

What apolipoprotein E allele variant is known to increasing the risk of Alzheimer’s disease?

A

E4

121
Q

hallmark features of AD

A

amyloid plaques, neurofibrillary tangles and neuronal loss

122
Q

What are the three genes that cause autosomal dominant forms of Alzheimer’s disease?

A

APP, PSEN1 and PSEN2

123
Q

What is the name of the prodromal stage that precedes Alzheimer’s disease dementia?

A

mild cognitive impairment

124
Q

What is the generic name referring to the catalytic activities that cleave the amyloid precursor protein to generate amyloid-beta peptides?

A

secretases

125
Q

What is the generic name referring to the catalytic activities that cleave the amyloid precursor protein to generate amyloid-beta peptides?

A

secretases

126
Q

stages of Alzheimer’s

A
  1. Normal
  2. Preclinical
  3. Mild cognitive impairment
  4. AD
127
Q

during mild cognitive impairment stage, what part of the brain is degenerating

A

Entorhinal cortex

128
Q

neuronal cell death starts in the _ stage of AD

A

mild cognitive impairment

lecture 1

129
Q

what broad parts of the brain cause clinical presentation of AD

A
  • hippocampus
  • prefrontal cortex
  • entorihinal cortex
130
Q

2 types of cognitive tests for AD

A
  • mini mental state exam (MMSE)
  • mini cog
131
Q

mini mental state examination (MMSE) is _ that indicates _

A

a Q&A test that is a specific indication of consiousness, speaking, memory, etc

132
Q

mini cog described

A
  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
Q

Gross anatomical changes in Alzheimer’s

A
  • atrophy - overall brain but effects hippocampus and EC more
  • neurofibrillary tangles
  • amyloid plaques
134
Q

amyloid precursor protein (APP) is cleaved by _ named _, _ and _

A

secretases named α, β, and γ

135
Q

amyloidogenic pathway

describe

A
  • γ and β secretases cleave in two places around Aβ gene
  • Aβ peptide made
  • β site cleavage
136
Q

non-amyloidogenic pathway

describe and why does it exist

A
  • α cleaves in the middle Aβ peptide
  • protective pathway to decrease probability of plaques being makes
  • no Aβ peptide made
  • α site cleavage
137
Q

pathway in cell of APP

A
  • APP secreted to cell surface from golgi
  • goes to sorting endosome if beta cleaved
138
Q

the tay gene undergoes _ and has _ isoforms

A

alternative splicing, has 6 isoforms

139
Q

tau normally

A

stabalizes and binds microtubles

140
Q

_ of tau causes it to not _ and instead form _

A

phsophorylation of tau makes it not bind to MT and instead form NFT

141
Q

clinical hallmark of ALS

A
  • upper AND lower motor neuron symptoms
142
Q

Tau NFTs affect the _ first then

A

affects entorhinal cortex and locus coerulus first then propogates upward into basal forebrain

143
Q

in AD, there is monoaminergic deficits in _ neurons that regulate

A

acetylecholine neurons that regulate mood, working memory, reward, associative learning

144
Q

progression in Braak staging of tau

A
  • start in EC
  • spread to limbic areas (stage 3ish)
  • spread to neocortical areas
145
Q

familial AD is broadly caused by

A

mutations in APP

146
Q

PSEN1 is

A

active catalytic site of gamma secretase

can be mutated in AD

147
Q

PEN2 and APH-1 are

A

modulators of gamma secretase

148
Q

NCT helps with

A

gamma secretase recognition of substrates

149
Q

early onset familial AD mutations are in

A

APP and PSEN-1

150
Q

late familial ADD onset mutation in

A

PSEN-2

151
Q

PS1-E280A mutation is

A

a mutation in a specfic gene pool in colombia that causes AD

152
Q

genetic risk factor for sporatic AD is mostly

A

APOE gene polymorphism

153
Q

sporadic AD risk factors

A
  • aging
  • genetics (APOE)
  • gender
  • excersise (reduce risk)
  • TBI
154
Q

_ is the non modifiable risk factor in sporadic AD

A

age

155
Q

having more copies of _ increases risk of sporadic AD

A

APOE4

156
Q

APOE is on chromosome _ and encodes _ alleles

A

chromosome 19, 3 alleles

157
Q

APOE has domains for

A

receptor binding and lipid binding

158
Q

what APOEallele reduces and raises risk of AD

A
  • ApoE2 reduces risk
  • ApoE3 neutral
  • ApoE4 increases risk
159
Q

Two of the most consistent pathological findings in EARLY stage Chronic
Traumatic Encephalopathy (CTE) are

A

focal deposits of phosphorylated tau and focal axonal varicosities in the cortex.

160
Q

Which genes linked to familial Amyotrophic Lateral Sclerosis (fALS) interfere with normal proteasomal or autophagic degradation?

A
  • SOD1
  • UBQLN2
  • TDP43
  • VCP
161
Q

In which cellular compartment does the Ɣ-secretase complex generate amyloid-β peptides from carboxyterminal fragments of APP?

A

late endosome/multivesicular body

162
Q

What are the major components of the Ɣ-secretase complex?

A
  • PSEN-1
  • PEN-2
  • NCT
  • APH-1
163
Q

APP overexpressing transgenic mice key features

A

Has:
* amyloid plaques
* selective neuronal loss
* cognitive decline

does not have tau mutations or atrophy

164
Q

limitations of APP & hTau over expressing mice

A

APP do not express tau mutations but when express tau find out that tau doesn’t cause AD so

165
Q

APP/MAPT knock in mice features and limitations

A
  • amyloid deposits shown
  • tau phosphorylation
    Limitations:
  • neuronal loss
  • no NFT
  • may or may not have memory deficits
166
Q

Amyloid plaques visualized by and shows

A

PiB:
* binds to plaques
* increased in frontal cortex and preculneus

FDG-PET:
* shows glucose utilization
* decrease glucose utilization in AD

167
Q

in AD, amyloid plaques increase in the

A

prefrontal cortex and preculneus

168
Q

structural brain changes with Alzeimer’s

A

hippocampus volume goes down

169
Q

a petient can have _ but still not have AD

A

amyloid plaques

170
Q

IN AD, _ level of A-beta _ is

A

CSF levels of a beta 42 is decreased 50%

171
Q

in CSF, _ used to diagnose AD

A

Abeta 42:40 ratio

172
Q

why is Abeta42 reduced in CSF of AD

A

plaques stay in brain so not filtering out in CSF

173
Q

in CSF, _ increased in AD

A

total tau increased 300%

174
Q

why does CSF higher t-tau in AD

A

because tau is phosphorylated and realeased from MT so it comes out in CSF

175
Q

CSF t tau shows _ while p tau shows _

A

ta tau shows intensity of neuroaxonal degeneration
pptau shows tangle pathology

176
Q

1st biomarker of AD that shows up is

A

amyloid plaques

177
Q

blood based test for AD shows

A

chance of having AD

178
Q

cholinesterase inhibitors _ and they are a _ treatment

A

inhibit breakdown of AceCh and are a symptomatic treatment

179
Q

tau path in AD brain

A

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
Q

_ mediates _ in AD

A

tau mediates Abeta induced deficits

181
Q

how do they know tau mediates abeta

A

when removed tau gene in AD mice, cognitive function improved

182
Q

familial AD vs sporadic when it comes to Abeta

A
  • familial: problems with abeta production (increase in abeta 42)
  • sporadic: failure of abeta clearance, increasing levels
183
Q

Abeta oligomers are

A

synaptic toxins

184
Q

proposed role of APOE in AD

A
  • tau mediated neurodegen (up)
  • neuronal toxicity (up)
  • Abeta clearance (down)
  • more a beta aggregation
  • down insulin signaling

NSCI 4501 (5 decks)

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