Dylan Terstege

A girl and her pet are watching the starry night sky, where some of the stars are the brain. a joshua tree on the left indicates the location

You KNOW you've arrived, mainstream, when your invention is turned into an open source asset!🧠🧪 Kudos @deryasargin.bsky.social www.eneuro.org/content/12/6... @cate-cholamine.bsky.social @mathiasvschmidt.bsky.social @zenbrainest.bsky.social @sfn.org #StressNeurobiology @carmensandi10.bsky.social

My first paper in the Sargin Lab 🥳 so grateful to have been able to work on this project

@deryasargin.bsky.social
@dterstege.bsky.social
@jonathanepp.bsky.social

A research team led by Dr. Jonathan Epp and Dr. Derya Sargin at the University of Calgary, funded by Brain Canada and Women’s Brain Health Initiative (WBHI), has identified a promising target for new Alzheimer’s disease treatments. bit.ly/45atSCf

Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease Altered function, connectivity, and survival of parvalbumin-expressing neurons in the retrosplenial cortex in Alzheimer’s disease.

Fantastic new paper on Alzheimer's Disease from my colleague @deryasargin.bsky.social and her team!
www.science.org/doi/10.1126/...

Thanks Liisa! 😁

Female brain holds the key to understanding Alzheimer’s disease. Epp-Sargin lab collaboration led by @dterstege.bsky.social featuring @liisagalea.bsky.social is out in Science Advances. We uncover the mechanisms that make females more vulnerable to Alzheimer’s - in mouse models and human brains 🧠

This wouldn’t have been possible without the contributions of my incredible lab mates and collaborators.

Many thanks to Yi Ren, Kabirat Adigun, the @ucalgarymed.bsky.social ASOC (Heewon Seo & Bo Young Ahn), @liisagalea.bsky.social, @deryasargin.bsky.social, and Jonathan Epp.

15/15

In summary, we:

Found sex-specific impairments in RSC PV-IN presentation in AD 👫

Characterized consequences locally and brain-wide 🌎

Demonstrated the clinical relevance of this phenotype 🏥

Improved cognitive performance by promoting the activity of RSC PV-INs 🎓

14/15

If dampening RSC PV-INs impairs cognition, can we improve memory performance by increasing the activity of these cells? 📈

By chemogenetically promoting the activity of RSC PV-INs, we improved contextual memory performance in aged female
5xFAD mice

13/15

How does this carry over to the clinic?

At rest, RSC activity should be highly correlated with the rest of the default mode network (DMN). Via clinical rs-fMRI scans, we noted increased density of anti-correlated RSC connections with DMN regions in AD.

(👀 the slopes of males vs females…)

12/15

Does dampening the activity of these cells induce similar changes to those seen in AD? 📉

Turns out, yes. With chemogenetic dampening, we impaired memory performance and increased the density of RSC anti-correlations (shown here in 🟢)

11/15

With c-Fos as a proxy of neuronal activity, we can study brain-wide functional connectivity (see: www.mdpi.com/2079-7737/12...).

In female 5xFAD mice, the density of anti-correlated RSC functional connections increases drastically (shown here in 🟢)

10/15

Let’s focus on memory impairments, such as those observed in 5xFAD mice.

Memory processes depend on networks of brain-wide activity. The RSC is involved in many such networks. PV-IN dysfunction may alter RSC connectivity - but how can we study this in freely-behaving mice? 🤔…

9/15

But what about in freely-behaving mice? 🐁

In vivo, my lab mate Yi Ren and I examined RSC PV-IN dynamics at both a population- and single cell-level. During a working memory task, we identified impaired RSC PV-IN activity in 5xFAD mice.

8/15

These transcriptional changes prompted electrophysiological characterization of RSC PV-INs ⚡️

These experiments were conducted by @deryasargin.bsky.social, who found impaired inhibitory control in RSC PV-INs of female 5xFAD mice.

7/15

But back to the paper:

Let’s dive deeper via gene-expression within PV-INs (GeoMx DSP) 🧬

Many genes critical to PV-IN function are down-regulated in female 5xFAD mice, particularly relating to GABA signalling and potassium transport

6/15

Parvalbumin as a sex-specific target in Alzheimer’s disease research – A mini-review Alzheimer’s disease (AD) is the most common form of dementia, and both the incidence of this disease and its associated cognitive decline disproportio…

Maybe this female-specific vulnerability of PV-INs to AD shouldn’t have come as a surprise?

From our recent review, these cells are highly sensitive to changes in circulating estrogens and are very vulnerable to metabolic disruption prevalent in AD 👫

www.sciencedirect.com/science/arti...

5/15

Gene expression does not always align with protein expression, so next we assessed PV-IN immunohistochemistry 🔬

Here, we noted earlier impairments in PV-IN presentation in female 5xFAD and similar patterns of impairment in human tissue samples

4/15

Altered metabolic activity often coincides with impairments to local neuronal and glial populations

With single-cell spatial transcriptomics (Xenium), we noted down-regulation of Pvalb and other PV-IN-related genes in the RSC of 5xFAD mice 🧬

3/15

Retrosplenial hypometabolism precedes the conversion from mild cognitive impairment to Alzheimer's disease INTRODUCTION Not all individuals who experience mild cognitive impairment (MCI) transition through progressive stages of cognitive decline at the same rate, if at all. Previous observational studies...

So, why the retrosplenial cortex (RSC)?

The RSC is involved in many learning and memory processes. Furthermore, as we previously demonstrated via clinical FDG-PET, hypometabolic activity in this region predicts cognitive decline 🧠

alz-journals.onlinelibrary.wiley.com/doi/10.1002/...

2/15

Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease Altered function, connectivity, and survival of parvalbumin-expressing neurons in the retrosplenial cortex in Alzheimer’s disease.

🚨New paper from the Epp and Sargin Labs!🚨

We identified early sex- and region-specific impairments to parvalbumin interneurons (PV-INs) during Alzheimer’s Disease (AD) pathogenesis

www.science.org/doi/10.1126/...

Simplified highlights below:

🧵/15

The new issue of Science Advances (open-access) has multiple papers on women's health. These 2 are related to menopause, hormone replacement and brain health
www.science.org/toc/sciadv/c...

SSRIs reduce plasma tau and restore dorsal raphe metabolism in Alzheimer's disease INTRODUCTION Tau pathology impacts neurodegeneration and cognitive decline in Alzheimer's disease (AD), with the dorsal raphe nucleus (DRN) being among the brain regions showing the earliest tau pat...

Our work on the effect of SSRIs on brain metabolic activity, tau levels and cognition is out. Another study led by amazing-Dylan Terstege (now Dr. Terstege).

alz-journals.onlinelibrary.wiley.com/doi/10.1002/...