Excessive local host-graft connectivity in aging 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 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 input from the appropriate brain regions for this area. Unexpectedly, we found a prominent several-fold increase in local inputs, in both amyloid-loaded and aged environments. State-of-the-art deep proteome analysis using mass spectrometry highlights complement system activation as a common denominator of environments promoting excessive local input connectivity. These data therefore reveal the key role of the host pathology in shaping the input connectome, calling for caution in extrapolating results from one pathological condition to another.

Brain injury environment critically influences the connectivity of transplanted neurons

“…However, stroke differs in many parameters from TBI and may hence influence connectivity differently, highlighting the need to examine quantitative connectivity specifically in different injury conditions. This is also confirmed by our accompanying manuscript ( 35 ), showing the influence of the aging brain and amyloid-loaded host environment in promoting the input connectome locally.…”

“…Note that every batch of RABV was tested in naïve C57BL/6J wild-type mice beforehand, and rare batches resulting in transduction of few cells in these experiments were not used in this study. Moreover, we have run in vitro controls that exclude changes in G protein levels in the transduced neurons by inflammatory stimuli, such as interferon-γ, LPS, and interleukin-1b in vitro ( 35 ). This is an important control because variable levels of G across conditions could result in different ability of the virus to spread and thus quantitative differences in connectivity.…”

“…We also appreciate the expert input by J. Kjell and M. Esgleas in the proteome analysis. We are particularly thankful to M. F. Martinez-Reza for performing a crucial experiment on testing inflammatory stimuli in regard to the regulation of the G protein, which we included in the accompanying manuscript by Thomas et al (35).…”

Commonly Overlooked Factors in Biocompatibility Studies of Neural Implants

“…Most biocompatibility studies are performed in healthy animal models, [ 256 ] particularly when histological performance is considered. However, recent studies of therapeutic cell transplantations have highlighted subtle differences in responses of neuronal network connections that arise in diseased and aged models even when no overt loss in neuron density or only minor differences in gliosis are noted, [ 75 ] and disparate connectivity behavior in inflamed and traumatically injured brains. [ 76 ] How these findings relate to implanted devices, other disease conditions, and human clinical applications remains to be determined.…”

“…[ 54 ] and are therefore not specifically covered in this review. Penetrative NI studies will be the primary focus of this review due to their ability to directly communicate with neural networks thus providing a metric for functional efficacy, their provisional clinical implementation, and similar wound healing‐related phenomena that undermine other technologies which involve penetrative surgical implementation (cell implantations, [ 71–76 ] biopsy collection, [ 77–79 ] microdialysis and drug delivery, [ 17,29 ] tissue‐engineered construct implantation, [ 80 ] to name a few).…”