K3 - key papers Flashcards
(35 cards)
Katzman 1988: no strong correlation between plaque severity and cognitive decline; some individuals have many plaques [PET] without memory impairment
- 137 care home residents, 55% have AD
- 10 subjects had cognitive performance in upper 20% and also showed pathology of AD with many plaques
- maybe started with larger brains so had larger cognitive reserve of neurons? but point stands, separate AD from plaques
also: Fagan 2009: PET study of 189 cognitive normal patients from 43-89 yo had no correlation between bran/CSF amyloid + psychometric test performance
first familial analysis of PD?
Polymeropoulos 1996
- contursi family, every patient but 1 had markers in chromosome 4
- multipoint linkage analysism markers 4q21-4q23 identified as PD phenotype
- 10% of family members had it
- SNCA was mapped to here, sequenced and found A53T change
- supported by SNCA triplication studies related to EOPD [Singleton 2003]
what is the prevalence of SNCA mutations in PD?
- seen in both monogenic and sporadic forms that a-syn is in LBs
- common SNCA risk variants present in ~40% Europeans, odds ratio ~1.3
what is evidence for PFFs seeding?
Chandra 2004:
- injection of PFFs into rodents -> behavioural dysfunction + SNc neurodegeneration
what did Periquet 2007 find?
a-syn variants without the NAC domain form no aggregates and are not toxic in drosophila model
- then expressed truncated a-syn which enhanced aggregation and neurotoxicity
describe Luk 2012 re. prion-like spread
- cultured exogenous a-syn injected nto striatum of WT mice
- converted their endogenous soluble counterparts into fibrils when internalised by neurons
- a-syn spreads to anatomically connected regions i.e. SNc develops LBs but not VTA
- accompanied by DAN loss, suggests good model
- only very few templates needed
what is evidence that endogenous a-syn is key to aggregation?
Kim 2019
* when a-syn KO mice exposed to a-syn fibrils, leads to no LBs, or impairment of synapses or neuronal connectivity
Flierl 2014
* in cells that are already pathological, use lentiviral vector carrying shRNA to downregulate SNCA in SNCA-Tri neuronal precursor cells
* reverses phenotypic intracell changes in metabolism + growth caused by PD
* though, unphysiological, NPCs subjected to forms of metabolic stress to get them to uptake shRNA
what is evidence that SNCA as well as a-syn is important in normal function?
- reduction in SNCA in rat can cause DAN loss + reduce cell viability
- need to maintain physiological SNCA but decrease misfolded a-syn: just stopping SNCA is a blunt instrument
what is the evidence that autophagy protects against neurotoxicity?
- Fussi 2018: if silence ATG5 and inhibit the autophagosome, you protect from neurotoxicity, as you increase the exocytosis pathway
- in cultued neurons w SNCA-OVX from adenoviral transduction + silencing with siRNA
what is evidence that type of a-syn mutation affects aggregation?
conway 2000
Conway 2000:
* familial PD’s A53T + A30P mutations accelerate formation of oligomers but inhibit further conversion of fibrils
* in vitro: A30P has limited vesicle binding so its availability may be higher in vivo, shown to suppress autophagy
what are other genes implicated in a-syn aggregation?
LRRK2: Chen 2012
* LRRK2 may phosphorylate MKKs upstream of MAPKs
* G2019S mutation of LRRK2 causes gain of function, overphosphorylation, overactivation of cell death pathway
* leads to DAN degeneration in mouse NSc
* though is induced mouse model - mice can’t get PD
what is evidence for PINK-1 and Parkin coinvolvement in a-syn pathology?
**Park 2006 **: if PINK-1 is KO’d, can reduce the effect by overexpressing Parkin
- PINK-1 builds up if mitochondria damaged, gets activated on mitochondrail surface, phosphorylates parkin
- parkin, activated by CaMKII, causes Uq ligase activity on mitochondria, tags it for degradation
- also UQs synaptojanin-1 -> vesicle recycling (iPSC studies)
- Uq is connected to relevant PD functions
**PINK-1 initiates signal for mitophagy, Parkin amplifies it **
what was the first large GWAS of PD?
2009: Simon-Sanchez
- 5000 white patients, 9000 controls
- exchanged data w Toda 2009, asian GWAS
- also found SNCA, but not MAPT
many GWAS loci are close to ‘monogenic’ PD genes: LRRK2, GBA, VPS13C
- rare coding variants here have high effect size, most common variants just increase risk
describe the age-at-onset GWAS of PD
Blauwendraat 2019:
* 28000 patients
* GBA + SNCA assocaited with younger onset
* MAPT + RAB29 associated with older
some pathways accelerate the underlying PD process? EOPD related to SNCA?
how was LRRK2 discovered to be linked to familial PD?
Zimprich 2004
* sequenced region of chromosome 12 in 46 families
* mutations of gene encoding LRRK2
* postmortem carriers showed DAN degenerative with diverse pathologies incl tau + a-syn
* LRRK2 is central to the pathogenesis of several major ND disorders
also implicated in sporadic PD:
* GWAS: 13,700 cases, 98,000 controls, LRRK2 among top suceptibility genes
what is function of Tau in healthy brain?
primarily stabilizes microtubules, neuronal internal scaffolding, ensuring proper transport of nutrients and other essential materials
what is the involvement of the protein degradation pathway in AD?
- defects in autophagy observed due to reduced expression of componenets
- results in decreased lysosomal activity, incr conc Uq protein and disruption of key signalling pathways
- Tau can cause endosomal defects in uptake and leakage, therefore aggregates need to be removed
what are some potential Tau targeting therapies?
- clinical efficacy yet to be established but multiple trials are ongoing
- usually immunotherapies for IC or EC, EC targeting alone likely to be less effective
- target Tau using: kinase inhibitors/phosphatase activators (PP2), to reduce tau hyperphosph
- or use caspase inhibitors to reduce cleavage (which promotes tau assembly + secretion and organelle dysfunction): minocycline + VX-765 have shown +ve results
- small molecule inhibitors of aggregation to NFTs: prevent/reverse aggregation to avoid changes in gene expression + synaptic loss seen w larger NFTs
what did Israel 2012 show?
- used iPSC-derived human purified neurons from familial (APPDp) and sporadic (sAD) patients
- observed sig. incr of AB, activated GSK-3B and p-tau vs control
- treatment w b-secretase inhibitors partially rescued the activated GSK-3B and p-tau, suggesting causative role for APP processing pathway, if not APP itself, in tau phosph
how have genetic studies highlighted the role of inflammation in AD?
AD: GWAS strongly + unbiasedly implicate immune-related genes + cell types + inflamm pathways [Jansen]
shifts understanding of sporadic AD pathogenesis by highloight immune component
what is evidence for a-syn overexpression affecting DA release?
Janezic et al 2013
* SNCA-OVX BAC transgenic mice have early, region-specific DA release deficits + altered vesicle distribution in axons
* independent of aggregation
where have sporadic risk genes for AD been found?
genes in APP processing: ADAM10, APH1B
- deposition of AB is a definitive pathological feature of sporadic AD
what happened with Doody’s 2013 and 2015 studies of y-secretase inhibitors for AD treatment?
- semagacestat tested in 2 large RCTs phase III in mild-moderate AD
- terminated both as ineffective or worsened decline, and also caused skin cancer
what happened with Gilman 2005’s anti-AB42 vaccine trial?
phase II in patients, RCT, placebo, n =372. 20% had antibody response. of the 8 who died after having vaccine, had lower AB load vs control, age matched
CSF tau decreased in responders vs placebo (smaller sample size)
halted due to safety concerns (meningoencephalitis)
did not show significant cognitive benefits or dementia ratings
