Alzheimer's disease Flashcards
Features of AD
- Memory impairment due to neuronal loss
- Decrease of Ach levels
- Increased glutamate excitotoxicity
- Proteotoxic stress
Major AD risk factors
- Age
- APOE (2-3 fold increase with one allele)
AD and amyloid
Characterised by deposition of amyloid beta peptide in extracellular compartment of the brain (ebwteen nerve cells) ion the form of amyloid plaques.
Secondary pathological changes occur in the neuronal cytoplasm, with accumulation of abnormally phosphorylated form of microtubule-associated protein tau.
This makes AD a secondary tauopathy.
Population frequencies of predominant APOE alleles:
o e2: 8.4%
o e3: 77.9%
o e4: 13.7%
o With 58.5% of the AD population being at least heterozygous for APOE 4.
- siRNAs as therapeutic strategy for AD: ADVANTAGES and LIMITATIONS
siRNAs - small interfering RNA.
ADVANTAGES: siRNA is a powerful tool for modulating gene expression through gene silencing. AI driven design, chemical modifications for better stability
LIMITATIONS: potential high off-target effects, unfavorable immune response, instability of naked siRNA, nuclease susceptibility and a need to develop a suitable delivery system
What have population studies shown about APOE
Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD
2 route of viral delivery
- intracisternal
- intraventricular (protein)
Outcome of viral gene therapy study (Rosenberg et al., 2018)
The data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions, intracisternal delivery of AAVrh.
10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention, thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS.
Viral vectors in AD
FOR AD viral vectors have been developed, e.g. recombinant adeno-associated viral vector (rAAV) and the HIV-derived lentiviral vector.
In these vectors, the viral genes for self-replication and, in the case of rAAV, incorporation of genetic material into chromosomal DNA, have been deleted.
AAVrh.10-APOE2 : target type and mechanism of action
- APOE
- Viral delivery of APOE2
AAVrh.10-APOE2: advantages and disadvantages
+ Single administration
+ Targeted delivery
- delivery issues
- do not cross BBB
- need invasive intrathecal injection
IONIS-MAPTRx: target type and mechanism of action
Tau
ASO, binds tau mRNA and inhibits translation
IONIS-MAPTRx: advantages and disadvantages
+ easy manufacture
+ can target at any site
- cytotoxicity
- requires chemical modifications
miRNAs: target type and mechanism of action
multiple targets
miRNA mimic of ASOs
miRNA: advantages and disadvantages
+ Simultaneous targeting of multiple AD-related pathways
- cannot be used to target 1 specific mRNA.
siRNA: target type and mechanism of action
BACE1, Tau, and other targets.
BBB-penetrating synthetic siRNAs.
difference between siRNA- and miRNA-based therapeutic agents
siRNA: one specific target, act by mRNA cleavage by endonucleolytic capacity
miRNA: multiple context-specific targets, and usually act by translational repression
siRNAs for AD therapy : study by Zhou et al
causes Glut1 overexpressed on luminal membrane.
- intracisternal route was the best route.
What are MIRs
mammalian-wide interspersed repeat
- repress tau translation by competing for ribosomal RNA pairing with the MAPT mRNA
What are NATs
natural antisense transcripts
- regulate epigenetic state, transcription, RNA stability or translation of overlapping egnes.
what is MAPT-AS1
brain-enriched NAT that is
conserved in primates and contains an embedded MIR.
Increased expression of the NAT-MIR (MAPT-AS1)
represses neuronal tau levels and is negatively correlated with tau pathology.
MAPT-AS1 - transcripts and expression during differentiation
MAPT-AS1 alternatively spliced transcripts share a common 3’end exon
MAPT-AS1 and MAPT expression INCREASES during neuronal differentiation.
tau repression is mediated by:
a MIR element
5’ AS pairing region complementary to MAPT 5’UTR.
MIR 7-mer motifs
these mediate tau translational repression
active translation - MAPT-AS1
two 7-mer motifs in MAPT IRES mediate abse-pariing with complementary motifs in the 18S rRNA, facilitating recruitment of 40S ribosomal subunit
repressed translation
tNAT1 binds to MAPT IRES via region of complementarity and competes with/blocks IRES binding to 18s rRNA.
ASO - MAPT
chemically modified ASO can be designed to target specific degradation of MAPT mRNA.
