8 - Neurodegenerative Diseases Flashcards
what is Alzheimer’s and who’s most likely to suffer
most common dementia type
White and women
symptoms of Alzheimer’s
memory loss/change
using inappropriate words
personality changes
problems with understanding and verbal tasks
risk factors of Alzheimer’s
alcohol
smoking
genetics
why is social isolation a risk factor of Alzheimer’s
no one to practice speech and understanding and not taking in social activities means cognitive functioning can’t be maintained
why is diet and physical activity a risk factor of Alzheimer’s
higher BMI and less physical activity correlate with lower cognitive health
why is poor education a risk factor of Alzheimer’s
not keeping brain active and is a strong predictor although could just be socioeconomic status
why does head trauma quicken the onset of Alzheimer’s
widespread plaques and having APOE4 gene reduces recovery
what is PD and its prevalence and incidence rates
second most common dementia with 1 in 500 having it and incidence being 1/12 of prevalence rate
what are some motor symptoms of PD
rigidity, forward tilt of trunk, shuffling gait, brady/hypokinesia
what are some non-motor symptoms of PD
impaired memory, fluctuating attention, impaired perception, mood problems
describe the gross pathology of Alzheimer’s
frontal/temp lobes lose volume
enlarged sulci
in Alzheimer’s, what does a loss in hippocampus mean
memory is affected and this correlates with rate of cognitive loss
in Alzheimer’s, what does reduces brain activity during facial recognition tests mean
there is no activity so people and places are confused
in Alzheimer’s, what does neuronal loss mean
decline in ChAT/cholinergic neurons impacting memory and cognition as less ACh
where are beta amyloid plaques and what do they do
in between cells and in synapses, interfere with cell communication
what are BAPs made of
amyloid precursor protein which is on chromosome 21 and is responsible for synapse formation and neuronal plasticity
what is APP split into
alpha, beta, gamma secretases
in the non-amyloid pathway, what processes happen
alpha secretase splits APP and then gamma secretase splits the strand in the membrane into 2
what happens in the amyloid pathway
beta-secretase cuts instead and then gamma-sec splits membrane strand into 2, including a B-amyloid strand
why does too much BAP lead to Alzheimer’s
they stimulate receptors responsible for apoptosis
why do more BAPs form
Presenilin 1/2 mutations responsible for gamma-sec
APOE4 mutation means BAPs not cleared up
BAP evidence related to C21
those with triple C21 develop it and have plaques
BAP evidence related to oligomers
they decrease synaptic density and cause long-term synaptic depression, impairing memory
evidence: what happens when B-amyloid is cultures in neurons
tau is produced
evidence against BAPs
B-amy found in those without Alzheimer’s, relationship with tau unclear, weak correlation between it and Alzheimer’s severity
evidence against BAP related to APOE4
it’s associated with other dementia types so not enough specificity
describe neurofibrillary tangles
made of tau, within cells, and affect nutrient movement and communication between/within nerve cells
what does tau do to microtubules
stabilises them by binding to 4 points
what happens when tau is hyperphosphorylated meaning it can’t bind to microtubules
tangles cause depolymerisation, impaired axonal transport, so neurotransmitters don’t get to terminal, nothing released, synapse dies, protein tangle left behind
what is the keychain for the tau hypothesis
health neuron damages, tau in neuron released, immune response triggered, microglia activated, cytotoxins released, more damage
evidence for tau hypothesis
tau levels correlate with AD severity
levels in CSF correlate with cognitive impairment
evidence of tau related to oligomers
tau oligomers found in those who develop Alzheimer’s
evidence for tay hypothesis related to treatment
those targeting tau are effective for cognitive impairment, symptoms treated using tau inhibitors in animals
what is the first part of the amyloid cascade hypothesis
b-a clumps into oligomers then plaques which get into synapses causing dysfunction so neuroinflammation occurs
neuroinflammation causes which cells tp be activated
microglial and astrocytic
what is the second part of the amyloid cascade hypothesis
balance of Ca2+/K+ ions disrupted, phosphatase + kinase activity altered causing tangles, neuronal dysfunction occurs, neurons die
PD: what happens when there is a mutation on chromosome 4
alpha-synuclein produced in pre-synaptic neurons affecting DA neuron synaptic transmission
why is synaptic activity affected by chromosome 4 mutations
aggregations form leading to Lewy bodies forming and a toxic gain of function since they’re toxic to the cell
PD: mutation for parkin prevents what
proteasomes receiving and destroying defective proteins so they build up and damage DA neurons instead
what gene codes for Lewy bodies
Park1
what risk factor of Alzheimer’s is also for Parkinson’s
repeated head trauma
how do oxidative stress and free radicals cause PD
imbalance with reactive O2 species production and their clearance damages DNA, lipids, proteins - DA neurons more susceptible
how are environmental toxins a risk for PD
can increase ox stress, mitochondrial dysfunction
what can pesticides do to cause PD
inhibit mitochondria through mutations and reactive oxygen species so misfolded a-synuclein builds up
how does MPTP contribute to PD development
striatal DA loss so less DA in subcortical regions, affecting the substantia nigra
what is the primary pathway in PD where most loss occurs
nigrostriatal pathway, which is where PD starts
what structure is affected in PD leading to less serotonin
serotonergic raphe nuclei
in PD, where are Lewy bodies present abnormally
cytoplasm
where are DA cells lost in PD
substantia nigra reticulata, which innervates basal ganglia, limbic forebrain, and cortex
subthalamic nucleus
globus pallidus
what division of the basal ganglia is affected most by DA loss in PD
putamen as losing DA affects motor skills since it receives excitatory glutamate from motor areas
describe receptors and role of the direct nigrostriatal pathway and indirect
D1 receptors, excites
D2 receptors, inhibits
describe keychain of what dopamine usually does in the direct nigrostriatal pathway
cortex and SNc exc striatum, which inhibits GPi/SNr, which inhibit the thalamus, which exc the cortex
describe the keychain of what dopamine usually does in the indirect pathway (motor loop)
cortex exc striatum, which inhibits the GPe, which inhibits the STN, which exc the GPi/SNr, which inhibits the thalamus, which exc the cortex
describe acetylcholinesterase inhibitors for treatment of Alzheimer’s
prevents ACh from being destroyed to improve motivation, memory, concentration but doesn’t affect neural degeneration
describe NMDA receptor antagonists for Alzheimer’s treatment
blocks glutamate activity and slows ACh neuron degeneration, slows symptom progression, helps w delusions, agitation
2 other Alzheimer’s treatments
psychosocial
antipsychotics
how can L-DOPA treat PD
affects DA neurons in the mesolimbic and mesocortical systems to control symptoms e.g. tremors, which can be done as more D2 receptors in striatum
why does L-DOPA need to be put in with dopamine decarboxylase inhibitor
so L-DOPA not converted to DA early but after it passes through b-b barrier as inhibitor won’t pass through
2 negatives of using L-DOPA
tyrosine hydroxylate is rate limiting so adding more L-DOPA won’t make a difference
wears off as more DA terminals lost in the long-term
describe using dopamine agonists to mimic DA action
work at post-syn DA receptors to reduce motor complications but are weaker than DA
how do MAOB and COMT inhibitors decrease dopamine breakdown
MAOB for early/late COMT for late both have symptom control and reduce motor complications but can’t control DA neuron degeneration
what’s one method to reduce motor complications only
decrease reuptake and increase release
why would the globus pallidus be destroyed to treat parkinson’s
less dopamine means more GP activity which inhibits the motor cortex through the subthalamic nucleus
how does deep brain stimulation work
STN/GP have rhythm imposed so they synchronise and reduce dyskinesias
how can transplanting foetal dopaminergic neurons from the substantia nigra help to treat parkinson’s
transplant into basal ganglia so differentiate into neurons, astrocytes, and oligodendrocytes to improve motor and bhvrl symptoms but Lewy bodies still spread
how can induced pluripotent stem cells be used to treat Parkinson’s
SCNT to differentiate into neurons, astrocytes, oligodendrocytes, and reinnervate host brain to improve motor function
stem cells are used to do what to treat Parkinson’s
development in dopamine producing nerve cells so dopamine can transmit nerve signals
how can gene therapy be used to treat Parkinson’s
prevents cell death and promotes regeneration by increasing L-DOPA/DA levels
what is the process in gene therapy to lower GP activity
insert GAD gene into virus, mix with extracted cells from patient and then reinsert
why is GAD used in gene therapy
it produces GABA which is inhibitory so it replaces excitatory glutamate neurons in the STN to decrease GP activity
issues with gene therapy
safety of viruses and gene expression
how can tremors and rigidity be treated
stereotactic neurosurgery to create lesions in the brain
