30 Jan 2020

Constipated endosomes are a hallmark of degenerating neurons in people with AD. Scientists blame crumbling retromers, complexes that normally flush proteins out of these little organelles. A study published January 22 in Molecular Neurodegeneration reported that stabilizing the retromer complex with a small molecule got endosomal trafficking moving again. Researchers led by Domenico Praticò of Temple University in Philadelphia reported that the compound also prevented Aβ deposition, tau hyperphosphorylation, synaptic loss, and memory deficits in a mouse model of amyloidosis.

R33, retromer chaperone, slowed Aβ deposition in 3xTg mice.

The small molecule lessened tau phosphorylation.

It prevented memory deficits in this strain.

Previous studies discovered that the retromer ushers amyloid precursor protein through endosomes, reducing APP’s exposure to amyloidogenic processing by endosomal BACE1 (Small et al., 2005; May 2008 news; Jun 2012 news).

Subsequently, Scott Small of Columbia University teamed up with Dagmar Ringe of Brandeis University in Massachusetts and Gregory Petsko at Weill Cornell Medical College, New York, to develop small molecules that bolster the complex. R33 and R55 fortified the interface between two of the three proteins that form the core of the retromer, vacuolar protein sorting-associated protein 35 and VPS26. The compounds, which the researchers called small-molecule chaperones, squelched Aβ production and tau hyperphosphorylation in cultured neurons from J20 mice, and in stem-cell-derived neurons from healthy volunteers and people with sporadic AD (Apr 2014 news; Chu and Praticò, 2017; Young et al., 2018).

In the new study, first author Jian-Guo Li and colleagues investigated whether these retromer “chaperones” could do the same in one strain of transgenic mice—3xTg, which express pathogenic versions of human APP, PSEN1, and MAPT genes. Starting when the animals were 3 months old, the researchers spiked their drinking water with R33 (also known as TPT-172), or with an inert control. Nine months later, R33 had lessened the mice’s deficits in working, associative, and spatial memory, the scientists reported. The compound even gave wild-type mice a memory boost.

Treated mice had slightly more synaptophysin, a marker of synaptic integrity, in their hippocampi than did untreated. R33 raised the concentration of VPS35, VPS26, and VPS29 to near normal levels, supporting the idea that the chaperone stabilized the retromer.

The compound roughly halved levels of Aβ, as well as BACE1-cleaved APP fragments sAPPβ and CTFβ. Phosphorylated tau levels were a quarter to a third lower than in untreated animals, depending on the epitope. The compound did not change levels of multiple kinases known to phosphorylate tau, including GSK-3β. Praticò told Alzforum that phospho-tau accumulates in endosomes, where it escapes degradation. The enhanced retromer function likely promotes phospho-tau degradation, he said.

“This recent study, along others that preceded it, validate what we had originally considered a remarkable observation: That stabilizing the binding of just two proteins in retromer’s cargo recognition core will enhance the overall function of a complicated, multimodular, trafficking machine,” wrote Small.

Petsko thinks the new data support the idea that the retromer could be targeted therapeutically. “Although the relevance of extreme transgenic models, like the one used here, to the human disease can (and should) be questioned, the ability of R33 to suppress the pathologies of the disease in vivo, including improving behavioral deficits, is impressive and suggests, as we have argued for many years, that endosomal trafficking in general, and retromer in particular, is a valid therapeutic target,” he wrote.

Petsko added that neither R33 nor R55 are likely to advance to clinical studies. Both are plagued by short half-lives and likely react with many other biomolecules. Praticò and Petsko both said they are working with medicinal chemists to find more suitable analogs for clinical development.—Jessica Shugart