Could we reverse memory loss in Alzheimer’s pa9ents? Mice

Aβ can affect the levels of certain molecules in the brain, one in parAcular is called Dickkopf-1 (Dkk1). This is interesAng because Dkk1 is an inhibitor of a family of proteins named Wnts, which have recently been suspected to be dys regu la ted in A l zhe imer ’ s d i sease . Importantly, an upregulaAon of Dkk1 is found in the brains of Alzheimer’s paAents. Also, Aβ elevates Dkk1 levels and blockade of Dkk1 protects synapses f rom Aβ-med ia ted degeneraAon. Our group decided to further invesAgate the effects of Dkk1 by varying its level in the brain. To achieve this, we used a laboratory technique widely used to engineer geneAcally modified mice that can produce different levels of a specific molecule at the scienAst’s will. To understand the effect of Dkk1 in the brain, we used a mouse which has more Dkk1 (let’s call it a “Dkk1-mouse”) than healthy mice. Hence, the Dkk1-mouse could mimic the changes brought on by Aβ.

Alzheimer's disease is the most common form of demenAa.A striking characterisAc is memory loss.In the brain, nerve cells or neurons make connecAons, named synapses, to process informaAon.When the synapses are not funcAonal or when the neurons are not well connected anymore, cogniAve deficits arise including loss of memory.
In Alzheimer's disease, a molecule called amyloid beta (Aβ), present in a healthy brain becomes deregulated and starts to accumulate in the brain of paAents forming the sadly wellknown amyloid plaques, one of the hallmarks of the disease.We know that Aβ induces synapse loss triggering deficit in memory, but how this occurs remains uncertain.
Aβ can affect the levels of certain molecules in the brain, one in parAcular is called Dickkopf-1 (Dkk1).This is interesAng because Dkk1 is an inhibitor of a family of proteins named Wnts, which have recently been suspected to be d y s r e g u l a t e d in Alzheimer's disease.Importantly, an upregulaAon of Dkk1 is found in the brains of Alzheimer's paAents.Also, Aβ elevates Dkk1 levels and blockade of Dkk1 p r o t e c t s s y n a p s e s f r o m A β -m e d i a t e d degeneraAon.Our group decided to further invesAgate the effects of Dkk1 by varying its level in the brain.To achieve this, we used a laboratory technique widely used to engineer geneAcally modified mice that can produce different levels of a specific molecule at the scienAst's will.To understand the effect of Dkk1 in the brain, we used a mouse which has more Dkk1 (let's call it a "Dkk1-mouse") than healthy mice.Hence, the Dkk1-mouse could mimic the changes brought on by Aβ.
The Dkk1-mouse with high levels of Dkk1 showed memory deficits.When we studied its brain, we saw a reducAon of the number and funcAon of synapses in the hippocampus, a brain area that controls learning and memory.As the only difference between the Dkk1-mouse and a healthy one was the presence of Dkk1, we concluded that Dkk1 induces the loss of synapses, their dysfuncAon and eventually the loss of memory.So, in short the more Dkk1, the more synapAc dysfuncAon, the greater decline in memory.
Given the levels of Dkk1 can be modulated in the Dkk1-mouse, we quesAoned whether the loss of synapses and memory are reversible.AYer memory loss, we restored the levels of Dkk1 back to healthy levels.By evaluaAng the performance of the Dkk1-mouse in memory tests and examining the state of the synapses, we observed that memory recovered back to normal and synapses regenerate.The funcAon of Dkk1 as a blocker of Wnts could be one possible explanaAon for these encouraging findings.Wnts are essenAal to maintain funcAonal synapses in the adult brain.Therefore, too much Dkk1 blocks Wnts leading to synapse loss and ulAmately memory loss.
These exciAng results suggest that by blocking Dkk1 levels even aYer the manifestaAon of cogniAve deficits, brain funcAon could be

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Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK This Break was edited by Massimo Caine, Founder & Editor in chief -TheScienceBreaker 1 of 2 TheScienceBreaker | Science meets Society TheScienceBreaker | Science meets Society restored offering a possible therapeuAc approach for the treatment of Alzheimer's disease.