Sachin Gadani

What accounts for the progression from healthy aging to Alzheimer's disease over an extended period of time?
The critical role of the immune system, particularly T cells and microglia.
A new, excellent review
www.cell.com/immunity/abs...

The Da Mesquita lab at Mayo Clinic (www.mayo.edu/research/lab...) is looking for a postdoctoral researcher to work on projects investigating the role(s) of the meningeal lymphatic vasculature in models of neurodegenerative diseases. Please spread the word and contact me in case you are interested! 😃

@jacksonmace.bsky.social

Huge thanks to the spectacular graduate student Dr. Jackson Mace who co-led this project, Dr. Peter Calabresi for guidance every step of the way, and all the co-authors and colleagues who helped with this work!

Stepping back, this project leads me to reconsider neuroprotective treatments in diseases like multiple sclerosis. We have good options for reducing relapse frequency, but no way to directly reduce neuron loss, and resulting disability, during flares or in progressive MS.

We found steps of the parthanatos cascade occurring in neurons during inflammation. Furthermore, blocking parthanatos with a targeted mutation or a small molecule protected some neurons for death.

Parthanatos is a death pathway exclusively triggered by excessive DNA damage. It starts with excess production of PAR and ends with [MIF](en.wikipedia.org/wiki/Macroph...) nuclease cleaving genomic DNA.

Thanatos - Wikipedia

We started with the observation that neurons have increased DNA damage in a model of neuroinflammation. This led us to parthanatos ("PAR" = poly-ADP-ribose + "thanatos" = well... [thanatos](en.wikipedia.org/wiki/Thanatos) ).

Autoimmune neuroinflammation leads to neuronal death via MIF nuclease-mediated parthanatos Nature Neuroscience - Neuroinflammation triggers DNA damage and subsequent parthanatos-mediated neuron death. Inhibiting parthanatos in a mouse model of autoimmune inflammation is neuroprotective...

How does inflammation kill neurons, and what can we do about it? Check out our latest paper where we consider this question: rdcu.be/e4nfP.

A Brief History of Oral Peptides Semaglutide is a peptide. Your stomach’s entire job is to destroy peptides.

seangeiger.substack.com/p/a-brief-hi...

Larner College of Medicine’s Dr. Peter Calabresi Elected to Prestigious National Academy of Medicine | Office of Medical Communications | The University of Vermont

www.uvm.edu/larnermed/me...

Totally agree! Comparative biology is 🔥

Reactivation of mammalian regeneration by turning on an evolutionarily disabled genetic switch 🧪

www.science.org/doi/full/10....

Peripheral infection wires T cells in the brain - Nature Immunology Research shows that previous peripheral microbial encounters can prime the entry of memory T cells into the brain, reshaping neuroimmune surveillance and altering seizure severity through microorganis...

www.nature.com/articles/s41...
Peripheral infection wires T cells in the brain 🧪

STAMP: Single-cell transcriptomics analysis and multimodal profiling through imaging Single-cell transcriptomics analysis and multimodal profiling (STAMP) by imaging enables single-cell analysis of cells in suspension without the need for sequencing. The markedly reduced costs and fle...

www.cell.com/cell/abstrac...
STAMP: Single-cell transcriptomics analysis and multimodal profiling through imaging 🧪

We are looking for a research technician to join our neuroimmunology group at the University of Pittsburgh. Please share to anyone who may be interested!

Posting: cfopitt.taleo.net/careersectio...

A route for cerebrospinal fluid flow through leptomeningeal arterial–venous overlaps enables macromolecule and fluid shunting - Nature Neuroscience The authors describe a mechanism for the clearance of macromolecules from cerebrospinal fluid in which macromolecules traverse from periarterial to perivenous spaces, at sites where intersecting lepto...

www.nature.com/articles/s41... 🧪

A route for cerebrospinal fluid flow through leptomeningeal arterial–venous overlaps enables macromolecule and fluid shunting

New Horizons for Multiple Sclerosis Therapy: 2025 and Beyond The advances achieved against multiple sclerosis (MS) represent one of the great success stories of modern molecular medicine. The development of therapies with increasing selectivity and safety, gui....

Very pleased to co-write this review with Bruce Cree and Steve Hauser on the future of #multiplesclerosis treatment

onlinelibrary.wiley.com/doi/10.1002/...

Prognostic Factors for Multiple Sclerosis Symptoms in Radiologically Isolated Syndrome This study attempts to identify prognostic factors at radiologically isolated syndrome diagnosis associated with the development of multiple sclerosis symptoms.

Prognostic Factors for Multiple Sclerosis Symptoms in Radiologically Isolated Syndrome

jamanetwork.com/journals/jam...

Increased CSF drainage by non-invasive manipulation of cervical lymphatics - Nature The outflow pathway of cerebrospinal fluid into lymph nodes in the neck and how non-invasive mechanical stimulation can enhance drainage and restore impaired outflow in aged mice are explored.

Increased CSF drainage by non-invasive manipulation of cervical lymphatics 🧪

www.nature.com/articles/s41...

"If the proposal is enacted, Americans today and tomorrow will be sicker, poorer, and die younger”
an $18 Billion cut
Only 3 NIH Institutes will remain in place, and even they will have their funds markedly reduced
www.statnews.com/2025/05/30/n...

Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development - Nature Neuroscience The choroid plexus (ChP) provides molecular cues for brain development. However, the underlying mechanisms are unclear. This study identifies an apocrine secretion mechanism in the ChP that modulates ...

Choroid plexus apocrine secretion shapes CSF proteome during mouse brain development 🧪

www.nature.com/articles/s41...

Pathways to Progressive Disability in Multiple Sclerosis: The Role of Glial Cells in Chronic CNS Inflammation Multiple sclerosis (MS) is the most common non-infectious inflammatory CNS disease, characterized by progressive neurodegeneration and focal demyelinated lesions. Traditionally considered an autoimmu....

Nice progressive MS review by Volker Siffrin:

Pathways to Progressive Disability in Multiple Sclerosis: The Role of Glial Cells in Chronic CNS Inflammation

onlinelibrary.wiley.com/doi/10.1002/...

Read our latest review article out in @thelancetneuro.bsky.social if you want to know more about CSF transport across the different compartments of the brain-meningeal border and its importance for neurological diseases with strong neuroimmune components 😉
authors.elsevier.com/a/1l7l75FFzL...

Progress toward Mitigating Disability Progression in Multiple Sclerosis | NEJM Multiple sclerosis is the most common cause of progressive neurologic disability in young adults. There had been no treatments for the disease, except for glucocorticoids, which were used for more ...

Insightful perspective from Dr. Calabresi @pcalabresi.bsky.social on recently published BTKi multiple sclerosis trials.

Progress toward Mitigating Disability Progression in Multiple Sclerosis

www.nejm.org/doi/full/10....

Inflammasome signaling in astrocytes modulates hippocampal plasticity The function of immune pathways in homeostatic neurobiology remains underexplored. Zengeler et al. find that the inflammasome complex, typically associated with immune responses, is involved in memory...

Excited to share our new work demonstrating a role for astrocytic inflammasome signaling in modulating hippocampal plasticity. @cp-immunity.bsky.social
All credit to Kristine Zengeler, who was the brains🧠 and muscle💪 behind this project and is a wonderful collaborator. www.cell.com/immunity/ful...

Very cool work--astrocyte inflammasomes are activated in the healthy brain (check out Fig 1a) and impact neurons through IL-33.

Inflammasome signaling in astrocytes modulates hippocampal plasticity The function of immune pathways in homeostatic neurobiology remains underexplored. Zengeler et al. find that the inflammasome complex, typically associated with immune responses, is involved in memory...

Inflammasome signaling in astrocytes modulates hippocampal plasticity 🧪
www.cell.com/immunity/ful...

Redefining CNS immune privilege - Nature Reviews Immunology In this Perspective, Smyth and Kipnis reappraise the concept of immune privilege in the central nervous system. Although immune privilege was originally thought to involve isolation of the central ner...

Redefining CNS immune privilege - Nature Reviews Immunology
www.nature.com/articles/s41...

Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease Hematopoietic stem cell transplant is the gold standard for treatment of globoid cell leukodystrophy, also called Krabbe disease. Aisenberg et al. define the molecular signature of disease-associated macrophages (globoid cells) and demonstrate that brain-specific high-efficiency macrophage replacement in the twitcher model of Krabbe disease improves neuropathology, macrophage dysfunction, and survival.

Online now: Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease