Biologic that disrupts PDE11A4 homodimerization in hippocampus CA1 reverses age-related cognitive decline of social memories in mice

Pilarzyk, Katy; Capell, William R.; Porcher, Latarsha; Rips-Goodwin, Audrey; Kelly, Michy P.

doi:10.1016/j.neurobiolaging.2023.07.008

Cited by 4 publications

(10 citation statements)

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“…PDE11A4 is strongly expressed in neurons of the ventral and dorsal hippocampus [3,4], the adjacent amygdalohippocampal and amygdalostriatal transition areas [5], the spinal cord, and the dorsal root ganglion [2], but not in any of the 20+ peripheral organs we have compared in young adult Pde11a KO versus WT mice to date [6]. Consistent with its particularly enriched expression in the ventral hippocampus, the best-known neurological roles for PDE11A4 are regulating social interactions, altering the formation of social memories, impacting neuroinflammation, and triggering age-related cognitive decline [3][4][5][7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 87%

“…As previously described [5,8,9], constructs were generated by Genscript (Piscataway, NJ, USA) that expressed either EmGFP alone containing an A206Y mutation to prevent EmGFP dimerization [51] or an EmGFP-tagged mouse Pde11a4 (NM_001081033) with the BamHI and XhoI recognition sequences added to the N-terminal and C-terminal, respectively. These constructs were initially generated on a pUC57 backbone and then subcloned into a pcDNA3.1+ mammalian expression vector using the BamHI and XhoI sites (Life Technologies; Walthan, MA, USA).…”

Section: Plasmid and Lentivirus Generationmentioning

confidence: 99%

Section: Plasmid and Lentivirus Generationmentioning

confidence: 99%

“…As previously described [5,9], constructs were subcloned into a proprietary "SPW" lentivirus transfer vector by the University of South Carolina Viral Vector Core using the restriction sites described above. The "SPW" backbone drives expression using the phosphoglycerate kinase 1 (PGK) promoter and is preferentially taken up by neurons even though it is a ubiquitous promoter in theory [5,9]. The lentiviruses delivered in 0.2 M sucrose/42 mM NaCl/0.84 mM KCl/2.5 mM Na 2 HPO 4 /0.46 mM KH 2 PO 4 /0.35 mM EDTA and the original titers were as follows: WT at 4.86 × 10 9 TU/mL, Y727C at 2.23 × 10 9 TU/mL, and M878V at 6.69 × 10 8 TU/mL.…”

Section: Plasmid and Lentivirus Generationmentioning

confidence: 99%

“…As previously described [5,9], the HT22 cells were grown in Dulbecco's Modified Eagle Medium (DMEM) with sodium pyruvate (GIBCO; Gaithersburg, MD, USA) supplemented with 10% filtered fetal bovine serum (R&D Systems, Bio-techne, Minneapolis, MN, USA) and 1% penicillin/streptomycin (GE Healthcare Life Sciences; Logan, UT, USA). The cells were passaged in T-75 flasks and incubated at 37 • C/5% CO 2 to reach 65-75% confluency.…”

Section: Cell Culturementioning

confidence: 99%

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The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme

Sbornova,

van der Sande,

Milosavljevic

et al. 2023

Cells

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Recently, a Y727C variant in the dual-specific 3′,5′-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

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Section: Introductionmentioning

confidence: 87%

Section: Plasmid and Lentivirus Generationmentioning

confidence: 99%

Section: Plasmid and Lentivirus Generationmentioning

confidence: 99%

Section: Plasmid and Lentivirus Generationmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

See 3 more Smart Citations

The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme

Sbornova,

van der Sande,

Milosavljevic

et al. 2023

Cells

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First Demonstration of In Vivo PDE11A4 Target Engagement for Potential Treatment of Age-Related Memory Disorders

Mahmood,

Eberhard,

Hoffman

et al. 2024

J. Med. Chem.

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PDE11A4 is a target of interest for the treatment of age-related memory disorders. A previous report from our laboratories described an amide series of potent, selective PDE11A4 inhibitors that was metabolically unstable. Investigation of heterocyclic amide isosteres for the labile amide moiety revealed distinct structure−activity relationships and identified several compounds with potency comparable to the amide series. This manuscript describes the characterization of structure−activity and structure−property relationships in this set, leading to the identification of an orally bioavailable, brain-penetrant, selective and potent PDE11A4 inhibitor. Target engagement experiments demonstrated PDE11A4 inhibition in the hypothalamus of mice that was absent in PDE11A4 knock out animals.

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Age-related increases in PDE11A4 protein expression trigger liquid:liquid phase separation (LLPS) of the enzyme that can be reversed by PDE11A4 small molecules inhibitors

Amurrio,

Patel,

Danaher

et al. 2024

Preprint

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PDE11A is a little-studied phosphodiesterase sub-family that breaks down cAMP/cGMP, with the PDE11A4 isoform being enriched in the memory-related brain region called the hippocampus. Age-related increases in PDE11A expression occur in human and rodent hippocampus and cause age-related cognitive decline of social memories. Interestingly, the age-related increase in PDE11A4 protein ectopically accumulates in spherical clusters that group together in the brain to form linear filamentous patterns termed ghost axons. The biophysical/physiochemical mechanisms underlying this age-related clustering of PDE11A4 are not yet known. As such, we determine here if age-related clustering of PDE11A4 may reflect liquid:liquid phase separation (LLPS), and if PDE11A inhibitors being developed for age-related cognitive decline can reverse this biomolecular condensation. We found that human and mouse PDE11A4 exhibit several LLPS-promoting sequence features including intrinsically disordered regions, non-covalent pi-pi interactions, and prion-like domains, with multiple bioinformatic tools predicting PDE11A4 undergoes LLPS. Consistent with these predictions, age-related PDE11A4 clusters were non-membrane bound spherical droplets that progressively fuse over time in a concentration-dependent manner. 5 different PDE11 inhibitors (tadalafil, BC11-38, SMQ-02-57, SMQ-03-30 and SMQ-03-20) across 3 scaffolds reversed PDE11A4 LLPS (a.k.a. remixing) in hippocampal HT22 cells, with PDE11A4 droplets reforming (a.k.a. de-mixing) following a 5-hour washout of low but not high concentrations of these compounds. Strikingly, a single oral administration of 30 mg/kg SMQ-03-20 substantially reduced the presence of PDE11A4 ghost axon in the aged mouse brain. Thus, PDE11A4 exhibits 4 defining criteria of LLPS, and PDE11A small molecule inhibitors reverse this age-related phenotype both in vitro and in vivo.

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Biologic that disrupts PDE11A4 homodimerization in hippocampus CA1 reverses age-related cognitive decline of social memories in mice

Cited by 4 publications

References 43 publications

The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme

The Sleep Quality- and Myopia-Linked PDE11A-Y727C Variant Impacts Neural Physiology by Reducing Catalytic Activity and Altering Subcellular Compartmentalization of the Enzyme

First Demonstration of In Vivo PDE11A4 Target Engagement for Potential Treatment of Age-Related Memory Disorders

Age-related increases in PDE11A4 protein expression trigger liquid:liquid phase separation (LLPS) of the enzyme that can be reversed by PDE11A4 small molecules inhibitors

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