Treating memory impairment Flashcards
LECTURE AIMS
- link cellular aspect of memory with memory loss
- target the synapse as a treatment option (forward and back translation)#
- examples of treating synaptic defecits in health and disease
what are ways in which dendritic spines have shown to be altered in disease
- decrease in desnity
- increase in density (autism)
- reduction in spine size
- distortion of spine shape
- formation of varicosities
Fiala et al, 2002
these lead to altered neural circuitry resulting in cognitive deficits
what is the justification of targeting synapses to treat memory impairments
Reverses the dendritic spine alterations seen in pathology will repair synapses leading to more normal/functional neural circuitry
What is forward vs. reverse translation?
FORWARD
- Start off with a disease, think about what pathways are involved. Model it in an animal to find a target.
- Create a novel drug
BACKWARD
- Start off with patient symptoms.
- Use it to find an existing drug that may adress symtppms
- Use animal models to improve the drug
Give an example of the forward translation approach (Fragile X)
E.g Trying to treat synaptic deficits in Fragile X syndrome
Fragile X syndrome:
- X linked neurodevelopmental disorder causing intellectual disability
- Also associated with ADHD, aggressive behaviour, seizures, hyperarousal
Cause:
- Caused by a breakage in the X chromosome, which is caused by an expansion of CGG repeats in FMR1 gene, which results in reduced production of the FMRP protein
- Fragile X is associated with an INCREASE in dendritic spines
- The FMRP protein is involved in controlling protein translation at synapses. If the FMRP protein is absent you get elavated levels of protein translation occurring.
- HYPOTHESIS - FMRP is there to limit local protein translation, which it does in response to mGluR receptor activation. Without FMRP, mGluR mediated protein translation is out of control leading to too many dendritic spines.
Treatment:
- mGluR agonist might reduce protein translation, normalize protein translation and reduce dendritic spines to normal levels
- E.g Michalon et al, 2012. Chronic inhibition of mGluR rescued behavioural and cellular deficits in fMR1 knockout mice
CON:
- Studies in humans revealed a lack of efficicy in treating humans with the mGluR antagonist
- why is this?
- Treatments often occured late on in life, missed developmental window
- Might have poor outcome measures, e.g questionairres
Give an example of the forward translation approach (Alzheimers disease)
- It has been suggesting that treating synapse loss in the preclinical stage of AD may be effective in reducing disease progression
- Post mortem examinations show decreased synapse density and abberant neurite sprouting
- Neuroimaging with synapse marker SV2A show that individuals with MCI have a reduction in synapses as marked by SCV2A
- Fausadil blocks synaptic loss driven by A-beta in AD, and this also improves memory impairments in mice (Sellers et al, 2018). This works because it is a Dkk1 inhibitor
What is an example of reverse translation?
- GWAS studies provide insight into genes associated with AD
- CMAPPING is a method where scientist give cells drugs and compare gene expression signatures in each cell, to get a database of how existing drugs impact gene expression
- This has allowed scientists to isolate drugs that have the ability to induce a gene expression profile which is in opposition to disease models.
- This highlighted that oestrogen may be useful in Alzheimers
- Watson et al tested and found that oestrogen normalized synaptic density in cells with a-beta
Evidence that oestrogen is protective in humans
Humans with schizophrenia given oestrogen show an improvement in positive symptoms
This might be because oestrogens increase synapse formation, and we know that ppl with schizophrenia have fewer synapses
What is a reverse translation way of using ISPCS
Read Readhead et al, 2018
