Neurodegeneration Flashcards
Neurodegenerative disease include:
Alzheimer's Parkinson's Huntington's ALS/MND Spinal muscular atrophy Creutzfeldt-Jakob Multiple sclerosis Other dementias
Protein aggregates in diseases are:
beta amyloid plaques
TAU tangles
alpha synuclein
TDP43
The most common cause of dementia is..
Alzheimer’s (62%)
Other dementias are..
vascular
mixed - AD/vascular
dementia with Lewy bodies
fronto-temporal lobe
Alzheimer’s mostly develops after the age of..
65
AD is not inherited but people with … have a higher risk. Why?
Down’s syndrome. They have 3 copies of APP (AD gene)
Genes predisposing AD are..
APP (amyloid precursor protein), APOE4 (carriers show more beta amyloid), PSEN1 and PSEN2 which encode components of the amyloid pathway.
The early symptoms of AD are:
Memory lapse due to damage in the hippocampus.
Problem-solving skills.
Language skills.
Visuospatial skills.
Other AD symptoms which can be subtle are:
inattentiveness cognitive dulling emotional withdrawal (apathy) agitation anxiety
Symptoms in later stages of AD become more … and include..
Severe:
delusions/hallucinations
dyspraxia
Pathologies in AD:
Cerebral atrophy Neurofibrillary tangles Plaques Cerebral amyloid angiopathy Gliosis
Pathologies of AD are staged by
Braak staging
B amyloid plaques can reside… They are detectable by..
In a neuron or diffuse extracellularly. IHC and silver stains
Neuritic plaques are surrounded by..
dystrophic cell body projections which label with TAU protein
Amyloid is thought to cause..(3)
induce neuronal death by apoptosis.
cause oxidative damage.
dysregulate Ca levels - injurying organelles.
Amyloid’s effect on neuronal circuits could develop before..
cells are lost (ex vivo rat shows synaptic loss as a response to amyloid levels)
TAU tangles are found..
found with plaques (normal ageing) and are intracellular
TAU tangles are seen in which diseases:
AD, FTDP, coriticobasal degeneration and Pick’s disease.
amyloid angiopathy is… and can cause..
amyloid deposition in blood vessels which cause cerebral haemorrhage
PSEN mutations cause…important for..
lysosomal dysfunction by changing the pH of lysosomes. Involved in autophagy.
In AD, mutations in … affect motor proteins from attaching cargo
GSK
Braak staging shows..
spatiotemporal pattern of degeneration
in AD, degeneration of the cerebrum usually starts in the..
temporal and parietal lobes. Other variants include visual - posterior occipito-parietal/temporal areas
25% of AD patients develop..
Parkinsonism
AD can be mistaken for: (6)
Major depression Cerebrovascular disease Inflammatory/metabolic disorders Changes to medial temporal due to infection or vascular insults Stroke Tumour
Current therapies targeting amyloid in AD..
have failed to stop cognitive deficits despite reduction in amyloid.
Ways of looking into pathogenesis are:
GWAS, immune system pathway mapping, cholestrol metabolism , synaptic dysfunction and TREM2 variants (microglia and inflammation).
3 major therapies used in AD currently are…
AChE inhibitors
NMDAr antagonists
Amyloid targets
ACh inhibs cause … in AD
increase ACh levels to stabilise cognitive function, mainly lost from the nucleus basalis of Meynert (Aricept)
NMDAr antagonists are .. and cause..
anti-glutamate drugs which slow progression by reducing Ca, mitochondrial dysfunction and oxidants (Memantine)
2 monoclonal antibodies used in AD to target beta amyloid:
Aducanumab
Solanezumab
Aducanumab is a human antibody which has..
a high affinity for aggregated forms. Shown success by reducing neuronal death (through microglia).
Solanezumab is a humanised antibody which has a higher affinity for … than…
Soluble monomeric forms rather than aggregated forms. In phase 3 trials but doesnt show many benefits.
Verubecestat in AD is a small molecule which targets..
BACE1 and BACE2, amyloid production pathway. Phase2/3 trials but show low efficiency
A core CSF biomarker for AD is…and shows
Abeta42. shows total tau, cortical amyloid deposition
temporal lobe lesions affect..
hearing language object recognition memory limbic system
Motor neurons travel from .. to..
Run from the brain, through the brainstem and spinal cord, and innervate effector muscles
Cell bodies of motor neurons are within..
the brain or spinal cord
Complex networks of motor neurons develops in… and…
In the embryo and do not get replaced
Motor neurons is caused by..in what tract
motor neurons die, muscles stop receiving signals from the brain and waste away.
Corticospinal tract.
MND involves degeneration of … and … which cause either…
UMN - motor cortex
LMN - anterior horns of spinal cord
Bulbar neurons - motor nuclei
UMN primarily causes lateral sclerosis. LMN cause muscular atrophy.
MND is associated with other diseases:
FTD
cognitive problems
Parkinsonism
oculomotor pathologies
MND affects … in the UK. and has a life expectancy of…
5000 people in the UK. Life expectancy of 2-4 years, can be up to 10 but rare.
Usual onset of MND is..
60-80 years, but all ages can be affected
Death from MND happens due to..
respiratory failure
bulbar dysfunction
bronchopneumonia
…% of MND is genetic. Genes are.. and are involved in 3 aspects..
10%. C9ORF - intron expansion. SOD1 TARDBP FUS protein homeostasis, RNA binding proteins and cytoskeletal proteins
Early symptoms of MND:
general weakness of limbs (75%).
Bulbar muscles - medulla (20%).
Respiratory onset (5%)
Symptoms of upper MND:
weakness and spasticity - constantly contracted and stiff.
Symptoms of lower MND:
weakness due to wasting of muscle and fasiculations - floppy limb
Symptoms of bulbar onset (MND):
slurred speech, dysphagia, jaw spasms, tongue fasiculations, teeth grinding
In MND, protein inclusions of…are seen in..
TDP43 seen in nuclei and neurofilaments
In mutant SOD1 (MND), mitochondria is seen to accumulate..and are also..
in cell bodies instead of along the axon. Seen with vacuoles and swelling in dendrites
Mutations affecting axonal transport in MND are…and leads to..
in dynactin complex components. This leads to build up of toxic waste
Intronic expansion mutations of C9ORF in MND show..
intra-nuclear RNA foci and cytoplasmic inclusions of p62 - ubiquitin binding protein. Inactivation causes abnormal microglia
MND patients with mutations of SOD1 and Fus are distinct because..
they show inclusions of abnormal SOD1 and Fus proteins since they fail to fold properly
Treatment for MND works by..eg..
reducing excitation and glutamate - Riluzole
Improving survival in later stages of MND is done by..
non-invasive ventilation - tube through trachea
Treatments in clinical trials for MND are..
antisense oligonucleotides and monoclonal antibodies through lumbar puncture
Current studies for MND..
iPSCs used in drug screens to study toxic glial cells by converting fibroblasts to neural progenitors.
What is spinal muscular atrophy?
Recessive motor neuron disease typically in infants.
What is mutated in spinal muscular atrophy?
SMN1 gene; SMN protein is not produced
In Spinal muscular atrophy, SMN2 is being overexpressed by … to cause…
antisense oligonucleotide called Nusinersen. This affects splicing of SMN2 so more SMN protein is made. It is administered by lumbar puncture.
Other ways of increasing SMN expression in SMA…
Antibodies
Viral vectors
Loss of … is seen in the spinal cord in MND
white matter
Gene silencing of SOD1 is being studied through..
using viral vectors, adenovirus. This can cross the BBB
Parkinson’s is characterised by neuronal loss in… which causes..
the substantia nigra. Reduces levels of dopamine
symptoms of Parkinson’s develop after..
80% of neurons are lost
general symptoms of Parkinson’s are..
stiffness, slow movements and tremors.
Other symptoms of PD are:
brady/akinesia. small-stepped gait. stooped posture. reduced arm swing. repeated movements. tremor at rest rigidity - dull ache
Parkinson’s tremor has features of..
present at rest and unilateral
Later staged symptoms of PD are:
on/off dyskinesia. choreiform movements (jerky). depression. dementia. anxiety. hallucinations. constipation. urinary incontinence
conditions with similar symptoms to PD are:
Normal pressure hydrocephalus - corrected by draining of CSF.
Essential tremor in the elderly - not at rest and no increased tone
Pathology of substantia nigra in Parkinson’s shows..
cell loss and Lewy bodies of a synuclein.
TDP43 deposits in nuclei.
Risk factors of PD are genetic and enrivonmetal. Toxins from pesticides such as MPTP have shown to … in dopaminergic neurons
inhibit Cl- channels - Cl- cant move in, can’t repolarise
Imaging has shown the mitochondrial network in PD is..
hyperfused, meaning lower activity of mitochondria
PINK and Parkin are regulators of..
mitophagy - degradation of mitochondria.
Loss of PINK1 generally causes..
mitochondrial dysfunction and increased sensitivity to oxidative stress.
PINK is normally degraded constantly. When mitochondria are non-functional…
PINK phosphorylates Parkin and ubiquitin on mitochondrial membranes. This prevents mitophagy.
LRRK2 mutants in PD inhibit..
autophagy
Main treatments for PD focus on..
compensating the loss of dopamine
The 3 types of dopamine treatment are:
LDOPA
Dopamine agonists
COMT/MAO-B inhibitors
Anti-cholinergics are also used in PD to..
reduce excitation in tremors. Not good, have side effects on cognition
L-DOPA is…and how is it taken?
the precursor of dopamine. It comes in 3 different preparations:
kick start morning
release throughout day
slow release at night
Dopamine agonists such as Ropinirole, Praipexole and Rotigotine are used as..
substitues for dopamine, targeting postsynaptic dopamine receptors. They are a first choice drug when treating younger patients (under 60).
MAO-B and COMT inhibitors both inhibit..
enzymes which breakdown dopamine - catechol-o-methyl-transferase and monoamino-oxidase (also ALDH).
Gene therapies in PD aim to…and use lentivirus to deliver..
replace dopamine. Lentivirus delivers tyrosine hydroxylase - enzyme which converts L-tyrosine to L-DOPA. Tested in small and large animals, and injected into putamen of Parkinson’s patients.
Oxidative stress pathway has been targeted in PD by..which targets..
Small molecules target the Nrf2/ARE pathway, activating protection against oxidative stress in neuronal cultures.
Long term medication in PD causes..
wearing off effect - on/off phases of dyskinesia
Huntington’s causes death …. after onset
15-20 years
the HD gene htt is..
located on chromosome 4 and is a trinucleotide polyglutamate repeat disorder (CAG)
Huntington’s is a … inherited disease of..
monogenic, autosomal dominant - passed on from either parent. Severe atrophy of the striatum and cortex.
Normal amount of CAG repeat is … too many causes what in HD?
35 repeats. Over 40 repeats cause over-production of huntingtin protein.
Age of onset of HD is.. correlates to..
30-50 years. number of CAG repeats
Regional patterning of huntingtin is mainly seen in..
the striatum but also in cortex
Physical symptoms of HD are:
Chorea - progressive.
Dystonia - fixed posture.
Myoclonus - jerky
Tics
Other symptoms of HD are:
Cognitive impairments:
slowness of thoughts.
apathy.
subcortical dementia
Chorea in HD occurs due to..
loss of inhibitory GABA neurons in basal ganglia; dopaminergic neurons more active causing movement
Pathologies seen in HD:
Atrophy of cerebrum, sulci and caudate nucleus.
Astrogliosis - vast proliferation.
Reduced astrocyte response to amyloid
Protein aggregates
Protein aggregates seen in Huntington’s are:
TAU
Beta amyloid
Alpha synuclein
Huntingtin
Expansions of trinucleotide repeats cause… Common expansions are..
Gain of function, autosomal dominant effects. Found in promoters, UTRs, introns and exons. Common repeats are polyglutamine and polyalanine.
Post mortem tissue of HD has shown abnormal..
mitochondrial morphology; less cristae, with prominent defects in CII, changes in mtDNA and Ca handling.
Mice with mutant htt have shown..
localisation of htt on outer mitochondrial membranes with CII defects and reduced O2 consumption. This correlates to CAG repeat length.
JNK is mutated in HD. It is an abnormally active…involved in..
Kinase involved in regulation of phosphorylation of kinesin and dynein activity.
It is thought that Htt has roles in:
Transcriptional regulation. Protein homeostasis. Oxidative stress. Axonal transport. Synaptic transmission Suppression of apoptosis
HD is treated by..
Antipsychotics: presynaptic release of dopamine, postsynaptic receptor activation.
Interference of vesicle storage. Tetrabenazine
Tetrabenazine works by reducing..
uptake of dopamine by presynaptic vesicles and depleting dopamine storage.
Tetrabenazine is not great as..
not a lot of improvement.
Many adverse effects - sedation, depression, anxiety, insomnia
Sulpiride, Olanzapine, Haloperidol work in HD as…
dopamine receptor antagonists to reduce abnormal movement
Dystonia (abnormal tone and posture) can be alleviated by..
Botulinum toxins and Clonazepam
Trials in HD are targeting mutant htt protein with..
small molecules and antisense oligonucleotides
Microglia are immune cells of the CNS. They make up…of the CNS and have … origin
1-15%. Originate from myeloid lineage (not neuronal).
Microglia respond in… and indicate..
a sensitive but non-specific way. They are pathological markers for disease
Features of TDP43 are..
amorphous, disordered, and have prion-like domains
Prions are..and have …formation
RNA binding proteins which self replicate and transmit disease. They form an amyloid fibril-like formation.
Lewy body dementia has symptoms of..
Fluctuating cognitive decline.
Visual hallucinations.
Parkinsonism.
Neuroleptic sensitivity.
In Lewy body dementia, Lewy bodies are found… and are made of..
neurons of neocortex, limbic system and brainstem.
They are made of alpha synuclein
Vascular dementia is caused by..
infarcts in small or large vessel. Dementia is dependent on the location of infarct.
Risk factors of vascular dementia are..
atherosclerosis; smoking, alcohol, hypertension, cardiac disease, diabetes and genetics.
Gliosis is..and can lead to..
proliferation of several types of glial cells (astrocytes, microglia and oligodendrocytes). Can lead to scarring
Astrocytes provide..
trophic support to neurons and show response to damage
Astrocytes expressing SOD1 mutations in MND are..
selectively toxic to motor neurons by releasing factors.
Glial cells expressing mutant htt in HD have reduced..
ability to protect htt mutated neurons
Microglia respond to damage by..which causes..
retracting and thickening their processes. They form a rounded amoeboid-like shape, and express different molecules to induce astrocytes.
Microglia have 3 states:
M0 - resting
M1 - active, toxic
M2 - active, wound healing
Neurodegenerative diseases are characteristed by clumps of … proteins. This also means there is reduced..
Ubiquinated. There is reduced function of ubiquitin proteasome systems
Protein inclusions start in specific areas due to selective vulnerability, and spread..how..
through the brain in a stepwise fashion, correlating with disease progression
Selective vulnerability in AD is in..
entorhinal cortical and hippocampal CA1 neurons. These are particularly vulnerable to energy deprivation.
Selective vulnerability in HD is in..
spiny striatal neurons which express Cav1.3 channels; mediate Ca influx
Selective vulnerability in MND is in…
Spinal motor neurons are prone to hyperexcitation as they have low expression of GABA receptors. They express Cav1.3 channels which mediate Ca influx
Pathology is thought to spread throughout the brain by..
affected neurons produce toxins, picked up by surrounding neurons.
OR areas get affected in turn
Amyloid fibril formations have the ability to recruit other proteins to become amyloidogenic in order to build what structure?
twisted, non-branching filaments of beta sheets. Structures are fibrillar or multimeric.
Spread of aggregates requires neurons to..
release and uptake from other neurons. May occur by secretory/endocytic pathways or across synapses.
TAU, alpha synuclein and TDP43 can be transported to other neurons how?
Through the axon antero/retrogradely. Seen through in vitro studies.
Injection of TAU or synuclein into the brain causes aggregates where?
in anatomical structures distant from site of injection, implying that neuronal connections are involved in spread of aggregates.
Recent studies have shown TAU, beta amyloid and synuclein have different conformational variants which show different…
seeding properties and different levels of neurotoxicity. This contributes to heterogeneity of neurodegen diseases.
Evidence to suggest that protein aggregates are toxic are..
Proteins are mutated in familial diseases
Evidence suggesting protein aggregates are not toxic is..
model organism studies have shown toxicity in the absence of aggregates, suggesting they may be protective.
Longer protein aggregates have a slower turnover which potentially..
overwhelms protein homeostasis and degradation pathways
Aggregates interact with other molecules, and can … other proteins
sequester. This affect transcription.
Aggregates interfere with what processes?
Axonal transport
Nucleocytoplasmic
In MS, remyelination of oligodendrocytes has been looked at through
stem cell screening
Mitochondrial dysfunction affects..
Glucose and oxygen supply.
Ca handling
Lysosomal degradation pathway is activated in cells in response to stresses:
when a cell is starved.
When damaged constituents are present (eg. aggregates).
To defend themselves from pathogens
Autophagy is regulated by..
basal turnover and stress responses
mTOR activity in autophagy is regulated by signals of:
nutrients. Growth factors. stress pathways energy pathways Inositol pathways cAMP, Ca and JNK pathways
In neurodegen diseases, autophagy is observed as dysfunctional as..
protein aggregates are tagged with ubiquitin but are not apoptosed
p62 is a receptor for … which is seen to be defective in neurodegen diseases.
autophagosomes
Knockouts in mice have shown that loss of essential autophagy proteins cause..
accumulation of aggregates and neuronal loss. Neurons are sensitive to loss of autophagy
Autophagy has been stimulated by … called rapalogs. These are inhibitors of…
small molecules which are inhibitors of mTOR
Axonal transport works by components:
microtubules
Kinesin
dynein
molecular motors work as..
ATPases, converting chemical energy to mechanical energy
Dynein has other chains which bind to..
cargo and dynactin - factor for cargo binding
Fast axonal transport is for..
synaptic vesicles and mitochondria (50-400mm/day)
Slow axonal transport pauses between movements and moves..
proteins and larger molecules
Abnormal and excessive activation of kinases in motor proteins are hallmarks of neurodegen diseases. EG:
p38 MAPK JNK GSK (In AD, MNS and HD)
Kinase mutations phosphorylate kinesin and dynein. Mutations cause mitochondria to…kinesin to be..and prevent cargo…
cluster around the nucleus.
Kinesin is released from microtubules (preventing transport). Prevents cargo from attaching to motor proteins.
When …… are mutated, it causes microtubules to become unstable, reducing transport
TAU, Spastin and Hsps
Gene therapy involves the use of… to carry genes or molecules
vectors: plasmids, nanoparticles, viral - lentiviral or adenoviral
