Dataset Information

Excessive local host-graft connectivity in aged and amyloid-loaded brain

ABSTRACT: Transplantation is a clinically relevant approach for brain repair, but much remains to be understood about influences of the disease environment in the host on transplant connectivity. To explore the influence of ageing and amyloid pathology in Alzheimer's disease (AD) we examined graft connectivity using monosynaptic Rabies virus tracing in APP/PS1 mice and in 16-18 month-old wild type mice. Neurons differentiated within 4 weeks and integrated well into the host visual cortex receiving input from the regions appropriate for visual cortex. Surprisingly, however, we found a prominent several-fold increase in local visual cortex input connectivity in both amyloid-loaded and aged environment. State-of-the-art deep proteome analysis using mass spectrometry provides first insights into the composition of environments promoting or not local exuberant input connectivity. These data therefore highlight the key role of the host pathology in shaping the input connectome calling for caution in extrapolating from one to another pathological condition.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Stefanie Hauck

LAB HEAD: Stefanie M. Hauck

PROVIDER: PXD023407 | Pride | 2022-08-12

REPOSITORIES: Pride

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Publications

Excessive local host-graft connectivity in aging and amyloid-loaded brain.

Thomas Judith J Martinez-Reza Maria Fernanda MF Thorwirth Manja M Zarb Yvette Y Conzelmann Karl-Klaus KK Hauck Stefanie M SM Grade Sofia S Götz Magdalena M

Science advances 20220610 23

Transplantation is a clinically relevant approach for brain repair, but much remains to be understood about influences of the disease environment on transplant connectivity. To explore the effect of amyloid pathology in Alzheimer's disease (AD) and aging, we examined graft connectivity using monosynaptic rabies virus tracing in APP/PS1 mice and in 16- to 18-month-old wild-type (WT) mice. Transplanted neurons differentiated within 4 weeks and integrated well into the host visual cortex, receiving ...[more]

PMID: 35687689

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Project description:The purpose of this study was to determine whether there were differences in gene expression in the hippocampus, a part of the brain involved in memory consolidation, between male mice with age-related memory deficits (SAMP8 mice) and control mice with no age-related memory deficits. The senescence-accelerated mouse (SAMP8) strain exhibits decreased learning and memory and increased amyloid beta peptide (Aβ) accumulation at 12 months compared to 4 months. To detect differences in gene expression in SAMP8 mice, we used a Control mouse that was a 50% cross between SAMP8 and CD-1 mice and which showed no memory deficits (50% SAMP8 mouse). We then compared gene expression in the hippocampus of 4 month and 12 month old SAMP8 and Control mice using Affymetrix gene arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the Long Term Potentiation (LTP) (6 genes), Phosphatidylinositol Signaling (6 genes), and Endocytosis (10 genes) pathways. The changes in LTP included MAPK signaling (N-ras, CREB binding protein, protein phosphatase inhibitor 1) and Ca-dependent signaling (PI receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through PI3-kinase, and Western blotting revealed phosphorylation changes in AKT and 70S6K. Changes in the Endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered genes expression in three SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways may provide new therapeutic targets in addition to targeting Aβ metabolism itself. Global differential profiling of hippocampal gene expression (4 month and 12 month old SAMP8 and Control mice) was performed using Affymetrix GeneChip® Mouse Genome 430 2.0 Arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the Long Term Potentiation (LTP) (6 genes), Phosphatidylinositol Signaling (6 genes), and Endocytosis (10 genes) pathways. The changes in LTP included MAPK signaling (N-ras, CREB binding protein, protein phosphatase inhibitor 1) and Ca-dependent signaling (PI receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through PI3-kinase, and Western blotting revealed phosphorylation changes in AKT and 70S6K. Changes in the Endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered genes expression in three SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways may provide new therapeutic targets in addition to targeting Aβ metabolism itself. 2-way ANOVA (2 x 2 conditions, n=4). First variable was age (4 and 12 months) and second variable was mouse strain (Control and SAMP8). This results in 4 groups: Control-4 month, Control-12 month, SAMP8-4 month, and SAMP8-12 month. Each group had 4 biological replicates (4 mice). The ”Control” mice were a 50% backcross of the SAMP8 mice with CD-1 mice (50% SAMP8 mice). These mice were closely related to SAMP8 mice but exhibited no memory deficits at 4 or 12 months. The SAMP8 mice had memory deficits at 12 months but not at 4 months.

Dataset Information

Excessive local host-graft connectivity in aged and amyloid-loaded brain

Publications

Excessive local host-graft connectivity in aging and amyloid-loaded brain.

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