Dementia study involving rapamycin

Pretty much too technical for me but some of the latest?

Engineering memory with an extrinsically disordered kinase

Synaptic plasticity plays a crucial role in memory formation by regulating the communication between neurons. Although actin polymerization has been linked to synaptic plasticity and dendritic spine stability, the causal link between actin polymerization and memory encoding has not been identified yet. It is not clear whether actin polymerization and structural changes in dendritic spines are a driver or a consequence of learning and memory. Using an extrinsically disordered form of the protein kinase LIMK1, which rapidly and precisely acts on ADF/cofilin, a direct modifier of actin, we induced long-term enlargement of dendritic spines and enhancement of synaptic transmission in the hippocampus on command. The activation of extrinsically disordered LIMK1 in vivo improved memory encoding and slowed cognitive decline in aged mice exhibiting reduced cofilin phosphorylation. The engineered memory by an extrinsically disordered LIMK1 supports a direct causal link between actin-mediated synaptic transmission and memory.


Yes, it is a complex read for the layman.
But, the bottom line is that it is beneficial in mice.

"Our approach is based on a safe and well-tolerated clinically approved drug such as rapamycin that (i) crosses the blood-brain barrier (68), (ii) activates the engineered proteins (19, 21, 69ā€“71), and (iii) has well-known beneficial effects on cognition (42, 45, 68), allowing a potential synergic beneficial effect for future translational applications.


Iā€™m excited for this study to finish up. REACH Clinical Trial - Biggs Institute


This paper is interessting! However to my understanding it has nothing to do with potential therapeutic effects of rapamycin other than that it obviously can penetrate the blood-brain barrier in mice.

They engineered their to be studied protein LIMK1 with a rapamycin responsive element to switch the function of LIMK1 on or off in the brain of mice. With this system they can have a look at the phenotypic changes that occure when LIMK1 is active vs. inactive. This gives an insight into the function of LIMK1 but not rapamycin.

At least that seems to be the main finding of this paper. As @desertshores pointed out they also referred to the known beneficial effect of rapamycin.

Here the respective text that lead me to this conclusion:

To generate a controllable LIMK1, we have used the extrinsic disorder. In this approach, a rapamycin-regulatable engineered protein domain (uniRapR) or light-oxygen-voltage-sensing domain 2 (LOV2) is used to transform a protein domain of interest into a ligand or light switch.
Because uniRapR is designed to be disordered in the absence of rapamycin, its insertion into the kinase domain causes a structural perturbation in the absence of rapamycin [Fig. 1B]. The delivery of rapamycin (or its non-immunosuppressive analogs) induces the disorder to order transition in uniRapR domain and thereby in the host domain. This conformational transition should activate LIMK1. Notably, rapamycin is blood-brain permeable; consequently, this system should provide exogenous control of LIMK1 in the brain in vivo.