Misha Zilberter

Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer’s disease - Molecular Neurodegeneration Background A significant proportion of individuals maintain cognition despite extensive Alzheimer’s disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals could reveal therapeutic targets for AD. Methods This study defines molecular and cellular signatures of cognitive resilience by integrating bulk RNA and single-cell transcriptomic data with genetics across multiple brain regions. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk RNA sequencing (n = 631 individuals) and multiregional single-nucleus RNA sequencing (n = 48 individuals). Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole-genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition. Results Transcriptomics and polygenic risk analysis position resilience as an intermediate AD state. Only GFAP and KLF4 expression distinguished resilience from controls at tissue level, whereas differential expression of genes involved in nucleic acid metabolism and signaling differentiated AD and resilient brains. At the cellular level, resilience was characterized by broad downregulation of LINGO1 expression and reorganization of chaperone pathways, specifically downregulation of Hsp90 and upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. MEF2C, ATP8B1, and RELN emerged as key markers of resilient neurons. Excitatory neuronal subtypes in the entorhinal cortex (ATP8B+ and MEF2Chigh) exhibited unique resilience signaling through activation of neurotrophin (BDNF-NTRK2, modulated by LINGO1) and angiopoietin (ANGPT2-TEK) pathways. MEF2C+ inhibitory neurons were over-represented in resilient brains, and the expression of genes associated with rare genetic variants revealed vulnerable somatostatin (SST) cortical interneurons that survive in AD resilience. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. Conclusions We have defined molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preserved neuronal function, balanced network activity, and activation of neurotrophic survival signaling. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable interneurons likely provides compensation against AD-associated hyperexcitability. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Thrilled to share that our paper “Molecular hallmarks of excitatory and inhibitory neuronal resilience to Alzheimer’s disease” is now out in Molecular Neurodegeneration!

👉 link.springer.com/article/10.1...

#Alzheimer #Resilience #Neuroscience

‘Mini analysis’ misrepresents changes in synaptic properties due to incomplete event detection Abstract figure legend Summary of the study where simulated recordings (left) were used to characterise the effect of incomplete detection on mini (mPSC) analysis. Recording noise levels (red) determ...

Our paper on 'mini analysis' is now published in @jphysiol.bsky.social
If you are recording mPSCs or sPSCs, I hope this helps with analysis. Interpretation of these datasets is not as easy as it seems..!
Happy to discuss if you are interested
physoc.onlinelibrary.wiley.com/doi/10.1113/...

Proud to present our new paper in @natmetabolism.nature.com

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases
lnkd.in/eVzFrmUY

Check out our open-access platform chock-full with iPSC- and 🧠 lipidomics data (www.neurolipidatlas.com).

It was great to visit and talk all things science — thank you Shannon for the invitation and for hosting me! Flying back after a whirlwind day with new connections, ideas, and even a bottle of only-in-Kentucky bourbon for the lab :)

A study of gene expression in the living human brain - Molecular Psychiatry Molecular Psychiatry - A study of gene expression in the living human brain

🤯 Postmortem vs Living brain
Due to the unavailability of brain tissue from living people, most such studies are performed using tissue from postmortem brain.
"Expression levels differed significantly for nearly 80% of genes,"🤯
www.nature.com/articles/s41...

Tau drives cell specific functional isolation of the hippocampal formation A major challenge in understanding Alzheimer's disease is linking changes that occur across different biological scales. For example, how do changes in individual neurons build into widespread network...

New preprint from the lab that I'm very proud of! We found mutant tau can disconnect neurons from their networks by temporarily silencing a neuron's activity. This leads to breakdown in the coherent activity between the hippocampus and entorhinal cortex. www.biorxiv.org/content/10.1...

Awesome news Andrew, congratulations! 🎉

Tau pathology reprograms glucose metabolism to support glutamatergic activity and excitatory imbalance Alzheimer's disease (AD) is not only characterized by amyloid-beta (Aβ) and tau pathology, but also by early and progressive disruptions in metabolism. Neuronal excitability is tightly coupled with me...

🔥New preprint from the lab! Led by @rileyirmen.bsky.social

Tau pathology reprograms glucose metabolism to support glutamatergic activity and excitatory imbalance

📍 biorxiv.org/content/10.1101/2025.07.25.666872v1

🧵 on how tau disrupts the metabolism–excitability balance in Alzheimer’s disease

Super interesting work Shannon - looking forward to discussing in person soon!

The NIH budget will INCREASE by $400 million — not slashed by 40%, as Trump proposed — according to a proposal by Senate appropriators, says Sen Murray.

"Some have asked if there will even be an NIH by [2029]. The commmittee's resounding message is yes—Congress has your back", she says.

Glycogen supports glycolytic plasticity in neurons | PNAS Glycogen is the largest energy reserve in the brain, but the specific role of glycogen in supporting neuronal energy metabolism in vivo is not well...

C.Elegans neurons use glycogen to sustain synaptic function in times of energy stress: Glycogen supports glycolytic plasticity in neurons | PNAS www.pnas.org/doi/10.1073/...

For #AAIC2025 attendees: #ADRD researcher starter pack! Thanks @tyk314.net for promoting me to share this again

go.bsky.app/22DpUEy

Looking for a postdoc or staff scientist with brain slice electrophysiology experience. If you or someone you know is interested in, message me.

Cell-type-directed network-correcting combination therapy for Alzheimer’s disease A multi-cell-type drug discovery strategy targeting dysregulated gene networks in neurons and glia identified letrozole and irinotecan as a combination therapy that significantly improved memory and r...

amazing new discovery by my @gladstoneinst.bsky.social and @ucsanfrancisco.bsky.social colleagues, on cell-directed combination therapy for Alzheimer's disease. Although having seen first-hand what irinotecan does, I wouldn't recommend it. Proof of principle impressive. www.cell.com/cell/fulltex...

High‐frequency oscillations >250 Hz in people with Down syndrome and associated Alzheimer's disease dementia INTRODUCTION Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, ...

Exited to share our new work! We found scalp high frequency oscillations (HFOs) in adults with Down syndrome, before the clinical onset of Alzheimer’s dementia and late onset myoclonic epilepsy.
HFOs may hold the key to earlier diagnosis #HFOnews
alz-journals.onlinelibrary.wiley.com/doi/10.1002/...

Intracellular metabolic gradients dictate dependence on exogenous pyruvate - Nature Metabolism Jackson et al. provide insight into how metabolic adaptations that accompany cell state transitions drive reliance on exogenous nutrient availability, focusing on pyruvate as a key metabolite in central carbon metabolism.

RESEARCH | B Jackson, @lydiafinley.bsky.social‬
@mskcancercenter.bsky.social‬

Metabolic adaptations that accompany cell state transitions drive reliance on exogenous nutrients
🧪
https://bit.ly/4nWqEsH ?utm_source=bluesky&utm_medium=social&utm_campaign=natmetab

Congratulations Tal, that's a huge relief!

a man with a mustache is sitting on a swing in a park ALT: a man with a mustache is sitting on a swing in a park

54 days and counting on re-submission reviews... also celebrating the one-year anniversary of our initial submission.

I feel seen

Fuelling synapses via lipid metabolism Nature Metabolism, Published online: 01 July 2025; doi:10.1038/s42255-025-01306-wSynapses have long been thought to rely exclusively on glucose metabolism for energy. In this issue of Nature Metabolism, Kumar et al. reveal that synapses can tap into fatty acid metabolism to fuel ATP production and maintain synaptic activity when glucose is limited.

ICYMI:

The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway The Christchurch mutation (R136S) in the APOE3 (E3S/S) gene is associated with attenuated tau load and cognitive decline despite the presence of a cau…

🚨Our new paper is out!🚨 We uncover a protective mechanism of the rare APOE3 Christchurch (R136S) mutation against tauopathy—by suppressing microglial cGAS–STING–interferon (IFN) pathway, a key inflammatory axis triggered by tau. www.sciencedirect.com/science/arti...

Awesome! Look forward to finally meeting in person and talking HFOs!

Kicking off the inaugural GRC Alzheimer’s disease meeting — excited for the science and the discussions ahead!

"But I am blown away by how much we have learned about Alzheimer’s over the last couple of years."—Bill Gates
www.statnews.com/2025/06/17/b...
"This is the moment to spend more money on research, not less."
Agree 💯
erictopol.substack.com/p/predicting...
erictopol.substack.com/p/the-breakt...

BREAKING: A federal judge in Massachusetts (the Reagan-appointed William Young) has declared the Trump administration's cuts to NIH grants — ostensibly over Trump's EOs on gender ideology and DEI — are "illegal" and "void." He's ordering many grants restored.

Brightly labelled pyramidal cells in the mouse retrosplenial cortex. Blood vessels are visible of various thicknesses in darker colours.

#neuroskyence folks: as my postdoc grant is running out soon, I am looking for new opportunities in systems neuroscience!

Keywords: patch clamp ephys, opto, mouse behavior, (in vivo) voltage imaging. Would love to return to the Basal Ganglia.

Sharing appreciated, and happy #FluorescenceFriday !

What's an acceptable (non-crazy) number of times to refresh a journal's manuscript tracking page while waiting for reviewer comments on a resubmission? Asking for a friend.

Don’t miss our latest 📝 with @chrislisgaras.bsky.social & Rick Staba on high-frequency oscillations in preclinical 🧠 disease models, with guidelines for recording, detection and analysis. journals.sagepub.com/doi/10.1177/...

Announcing an official fundraising campaign to support my lab’s research on APOE4 and Alzheimer’s disease: joinus.cuimc.columbia.edu/participant/.... This campaign is itself an experiment of sorts. But mostly, it's an attempt to save my lab during an unprecedented time of turmoil in academia. 1/9

Early neuronal reprogramming and cell cycle reentry shape Alzheimer's disease progression https://www.biorxiv.org/content/10.1101/2025.06.04.653670v1