Neurodegenerative diseases Flashcards
(16 cards)
What is the pathophysiology of Alzheimers?
1) accumulation of amyloid-beta (Aβ) plaque deposits from abnormal cleavage of amyloid precursor protein (APP): deposits disrupt neuronal communication, trigger inflammation, and contribute to synaptic dysfunction and cell death.
2) neurofibrillary tangles, from hyperphosphorylated tau protein in the brain: impair axonal transport, disrupt cell structure, and eventually lead to neuronal death
3) Microglia and astrocytes are activated by plaques and tangles, release pro-inflammatory cytokines which exacerbates neuronal damage
What is the pathophysiology of Parkinsons?
Idiopathic, but tremors/bradykinesia/rigidity are due to loss of dopaminergic neurons projecting from the substantia nigra pars compacta to the striatum, dysrupting basil ganglia direct and indirect pathways, resulting in increased inhibition of the thalamus
Lewy bodies from misfolded alpha synuclein, ROS from mitochondrial dysfunction, neuroinflammation from active microglia releasing pro-inflammatory cytokines, all cause DA neuron death
Loss of dopamine in the pars compacta increases the overall excitatory drive in the basal ganglia, disrupting voluntary motor control and causing the characteristic symptoms of PD.
How is immunotherapy used in Alzheimers? What are the limitations?
Immunotherapy can involve injecting Aβ antigens (active immunization) or anti-Aβ monoclonal antibodies (passive immunization) to promote clearence from the brain, thought that clearing brain Aβ plaques may treat AD and stop disease progression
eg lecanemab: targets soluble amyloid-beta (Aβ) protofibrils, which are toxic intermediate aggregates, for phagocytosis and microglia clearence
Adverse effects like Amyloid-Related Imaging Abnormalities (ARIAs), including cerebral edema (ARIA-E) and microhemorrhages (ARIA-H), can outweight the pros. ARIAs more susceptiable in individuals with APOE ε4 allele
This approach is part of developing disease-modifying therapies (DMTs) that aim to change the underlying pathophysiology of AD
What is the pathophysiology of huntingtons?
Caused by CAG trinucleotide repeat expansion in the HTT gene on chromosome 4, results in abnormally long polyglutamine (polyQ) tract in HTT protein, causing it to misfold
HTT aggregates in the striatum and cortex cause synaptic dysfunction, cellular stress, and cell death, especially medium spiny neurons in the striatum causing direct and indirect pathway dysfunction (like Parkinsons) causing bradykinesia and rigidity
In other areas, neurodegeneration results in cognitive decline, physchiatric symptoms, and motor symptoms
More repeats → worse toxicity → earlier onset (anticipation)
What are the current therapies for Parkinsons and why is therapeutic development needed?
What are the current therapies for Alzheimers and why is therapeutic development needed?
What are the current therapies for Huntingtons and why is therapeutic development needed?
How is gene therapy used in Huntingtons?
What are new developing therapies for alzheimers disease?
What are issues in diagnosing neurodegenerative diseases?
How is Next-gen sequencing involved in neurodegenerative diseases?
WES or WGS is used to
- screen for families with inherited forms of neurodegeneration
- Identify rare or novevl mutations
- Identify biomarkers (eg miRNA in CSF or blood)
RNA-seq is used to unconver dysregulated pathways (eg inflammation/synaptic function)
What are some advances in sequencing technologies for amyotrophic lateral sclerosis (ALS) research?
How have organoids and iPSCs influence neurodegenerative disease research?
1) Organoids offer patient specific disease modeling: eg organoids w AB plaques and tau tangles for alzheimers
2) Brain organoids offer mechanistic insight: eg LRRK2 iPSC dopaminergic neurons for PD research
3) iPSCs used for high-throughput drug screening/genetic testing
How have single cell and spatial transcriptomics contributed to neurodegenerative disease research?
1) Cell-type specific expression profiling: eg discovering disease-associated microglia in Alzheimers
2) Detected vulnerable cell populations: eg transcriptional changes in motor neurons show dysfunction before overt dysregulation
3) Spatial: helps map gene expression to brain architecture
What is the role of the gut microbiome in alzheimers disease?
- Gut bacteria can alter AB aggregation
- Gut bacteria can produce LPS that trigger inflammation in the brain
- Gut bacteria can produce SCFAs that are neuroprotective and anti-inflammatory
- AD patients have dysregulated microbiome (lower diversity, inc pro-inflammatory bacteria)
- Fetal microbiota transplant improve cognition and reduce inflammation in animal models
What were the results from the two stem-cell therapy clinical trails for neurodegenerative diseases?
