Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model
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Evaluation Summary:
This is interesting and potentially impactful work uncovering mechanisms of stem cell exhaustion and impaired self-renewal that precede inflammatory phenotypes in Alzheimer's disease. The authors describe a mechanism converging on BMP signaling that may represent an early therapeutic target. The reviewers of this manuscript were excited about the potential impact but had some concerns which, if addressed, will strengthen the conclusions reached in this work.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.
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Evaluation Summary:
This is interesting and potentially impactful work uncovering mechanisms of stem cell exhaustion and impaired self-renewal that precede inflammatory phenotypes in Alzheimer's disease. The authors describe a mechanism converging on BMP signaling that may represent an early therapeutic target. The reviewers of this manuscript were excited about the potential impact but had some concerns which, if addressed, will strengthen the conclusions reached in this work.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Reinitz et al use APP transgenic mice and fetal neural progenitor cells expressing mutant APP to document an neurogenesis defect in which APP mutant cells proliferate early but have reduced regenerative capacity. This reduced regenerative capacity is measured by the ability of neural progenitor cells to form neurospheres. This correlated with the increased expression of Cdkn2a in with age and aberrantly increased expression in the APP transgenic mice. Crossing the APP mice with Cdkn2a knock-out mice reversed these deficits as did crossing the APP mice with mice haploinsufficient for USP16, a gene that promotes Cdkn2a expression. RNAseq analysis showed that USP16 haploinsufficiency also rescued aberrant increases in the BMP signaling pathway occurring in the APP transgenic mice. Inhibition of BMP signaling …
Reviewer #1 (Public Review):
Reinitz et al use APP transgenic mice and fetal neural progenitor cells expressing mutant APP to document an neurogenesis defect in which APP mutant cells proliferate early but have reduced regenerative capacity. This reduced regenerative capacity is measured by the ability of neural progenitor cells to form neurospheres. This correlated with the increased expression of Cdkn2a in with age and aberrantly increased expression in the APP transgenic mice. Crossing the APP mice with Cdkn2a knock-out mice reversed these deficits as did crossing the APP mice with mice haploinsufficient for USP16, a gene that promotes Cdkn2a expression. RNAseq analysis showed that USP16 haploinsufficiency also rescued aberrant increases in the BMP signaling pathway occurring in the APP transgenic mice. Inhibition of BMP signaling also rescued neurogenesis phenotypes in human fetal neural progenitors that expressed an APP mutation. Thus, the authors claim that decreasing expression of USP16 is beneficial and a potential therapeutic target because it acts on these two independent pathways, Cdkn2a (senescence) gene expression and BMP signaling. For the most part the data presented in this work supports the conclusions and is informative for the field. A conceptual weakness is how this may relate to late-onset SAD which is not caused by APP mutations. Finally, the claim that these two USP16-impacted pathways are completely independent could be strengthened by experiments testing whether Cdkn2a expression is affected when APP transgenic neural progenitor cells are treated with BMP inhibitors.
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Reviewer #2 (Public Review):
Reinitz et al., present evidence that cell intrinsic NPC defects predate neuropathological hallmarks of a mouse model of Alzheimer's disease. They found that their is a limited capacity for neurosphere formation from NPCs extracted from mice harboring APP mutations (Tg-SwDI model). Importantly, these NPC defects occurred prior to observable neuropathological hallmarks or cognitive defects associated with this model suggesting that these NPC defects are cell intrinsic. The authors extended these findings by demonstrating that impaired NPC self-renewal occurs in human fetal NPCs expressing APP mutations. Tg-SwDI mice showed Cdkn2a, a gene associated with inhibition of NPC self renewal, was increased. Tg-SwDI mice lacking Cdkn2a showed rescue of the NPC self renewal defect, suggesting this pathway could be …
Reviewer #2 (Public Review):
Reinitz et al., present evidence that cell intrinsic NPC defects predate neuropathological hallmarks of a mouse model of Alzheimer's disease. They found that their is a limited capacity for neurosphere formation from NPCs extracted from mice harboring APP mutations (Tg-SwDI model). Importantly, these NPC defects occurred prior to observable neuropathological hallmarks or cognitive defects associated with this model suggesting that these NPC defects are cell intrinsic. The authors extended these findings by demonstrating that impaired NPC self-renewal occurs in human fetal NPCs expressing APP mutations. Tg-SwDI mice showed Cdkn2a, a gene associated with inhibition of NPC self renewal, was increased. Tg-SwDI mice lacking Cdkn2a showed rescue of the NPC self renewal defect, suggesting this pathway could be exploited to rescue associated disease phenotypes. Due to potential negative effects of Cdkn2a loss, the authors demonstrated another protein associated with the BMI1/Cdkn2a pathway could be targeted. The authors found that genetic reduction of USP16 mitigated the NPC self renewal defects and rescued cognitive deficits in the Tg-SwDI. The findings presented by the authors provide compelling evidence that NPC self renewal defects are an early phenotype in AD and potential therapeutic target.
The data presented by the authors support their conclusions and provide an exciting potential therapeutic avenue, however incorporation of additional data would further strengthen their conclusions and the manuscript.
Determine whether reduction of Cdkn2a leads to increased neurosphere formation capacity in WT in Fig 3A. Is this rescue of NIC frequency specific to the Tg-SwDI, or does it result in a more general increase in NPC self renewal?
The author should include WT APP as a control in the analysis of pSMAD1/5/8 positive cells and its subsequent reduction by LDN-193189 in Fig.5.
The authors should include representative images of GFAP and Thioflavin staining used for quantification in Fig. 6
The authors' conclusion that Tg-SwDI/Usp16+/- rescues cognitive defects rely on one test and would be strengthened by additional cognition tests.
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Reviewer #3 (Public Review):
Clarke and colleagues describe early neural stem cell defects in a transgenic mouse model for rare familial variants of Alzheimer's disease. They described that early, long before the onset of typical Alzheimer symptoms, the mice show an initial over-proliferation of stem cells, which is followed by an exhaustion of stem cells and downstream impairments. They next show that manipulation of proteins that have been studied extensively in the context of proliferation can alleviate the phenotype. A particular strength of the manuscript is the dogma-free approach and the general frame of the study is highly innovative. However, the authors make several assumptions that are not sufficiently backed-up by the data.
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