Shannon Macauley

Tau pathology reprograms glucose metabolism to support cortical hyperexcitability, excitatory/inhibitory imbalance, and sleep loss npj Dementia - Tau pathology reprograms glucose metabolism to support cortical hyperexcitability, excitatory/inhibitory imbalance, and sleep loss

New work from our lab! Link: rdcu.be/e0sfU

𝗧𝗮𝘂 𝗛𝗶𝗷𝗮𝗰𝗸𝘀 𝗕𝗿𝗮𝗶𝗻 𝗠𝗲𝘁𝗮𝗯𝗼𝗹𝗶𝘀𝗺, 𝗗𝗿𝗶𝘃𝗶𝗻𝗴 𝗦𝗹𝗲𝗲𝗽 𝗟𝗼𝘀𝘀 𝗶𝗻 𝗔𝗹𝘇𝗵𝗲𝗶𝗺𝗲𝗿’𝘀 𝗗𝗶𝘀𝗲𝗮𝘀𝗲

A quick thread on our findings!

Thanks, Misha! Would love your thoughts. We're interested in how this layers on with APOE!

Thanks to my funders: NIH, NIA, BrightFocus, CART Fund

Big congratulations to our team! @rileyirmen.bsky.social for leading this works. Collabs: @johnsonlab.bsky.social Adam Bauer, Dan Lee, Pat Sullivan, Velu, and all coauthors!

Together, these findings reveal that tau disrupts sleep not by starving the brain of energy, but by misusing or misdirecting it. By linking tau pathology to glycolytic flux , hyperexcitability and sleep loss, this work suggests new targets to restore sleep in Alzheimer’s disease & tauopathies.

We used quantitative EEG analysis to assess changes in sleep macro and micro-architecture. We found tau pathology disrupts NREM and REM sleep, specific to the light period, but compromising beta activity which normally reflects cortical synchrony and GABA activity.

EEG recordings confirmed this state of hyperexcitability and lack of coordination among brain networks, while wide field optical imaging showed exaggerated responses of excitatory neurons to sensory stimulation, despite less glutamatergic neurons, confirming hyperexcitability in the system.

By tracing how glucose is used in the brain, we discovered that tau redirects glucose toward making glutamate and not ATP. This increased excitatory activity, reduced inhibition. This creates E/I imbalance that favors overexcitation, even though brain's mitochondria remains intact.

In this study, we show that tau pathology rewires how the brain uses energy, causes hyperexcitability, network desynchrony, and sleep loss. In mice, we found that tau surprisingly preserves normal body-wide metabolism and daily fluctuations in metabolic rhythms typically lost with aging.

Alzheimer’s disease is best known for a buildup of amyloid plaques and tau tangles in the brain, but long before memory problems appear, the sleep patterns begin to change. How these early changes emerge- especially how tau affects brain metabolism and sleep- has been unclear.

Tau pathology reprograms glucose metabolism to support cortical hyperexcitability, excitatory/inhibitory imbalance, and sleep loss npj Dementia - Tau pathology reprograms glucose metabolism to support cortical hyperexcitability, excitatory/inhibitory imbalance, and sleep loss

New work from our lab! Link: rdcu.be/e0sfU

𝗧𝗮𝘂 𝗛𝗶𝗷𝗮𝗰𝗸𝘀 𝗕𝗿𝗮𝗶𝗻 𝗠𝗲𝘁𝗮𝗯𝗼𝗹𝗶𝘀𝗺, 𝗗𝗿𝗶𝘃𝗶𝗻𝗴 𝗦𝗹𝗲𝗲𝗽 𝗟𝗼𝘀𝘀 𝗶𝗻 𝗔𝗹𝘇𝗵𝗲𝗶𝗺𝗲𝗿’𝘀 𝗗𝗶𝘀𝗲𝗮𝘀𝗲

A quick thread on our findings!

Plasma extracellular vesicles from APOE3 Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease INTRODUCTION The PSEN1E280A mutation causes autosomal dominant Alzheimer's disease (ADAD) with predictable onset, enabling presymptomatic studies. Extracellular vesicles (EVs) are emerging biomarker.....

Plasma extracellular vesicles from APOE3 Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease alz-journals.onlinelibrary.wiley.com/doi/10.1002/...

Immunometabolism in obesity: Understanding the beneficial and detrimental roles of inflammation Chronic low-grade metabolic inflammation (known as metaflammation) drives insulin resistance and metabolic dysfunction in obesity. This Essay discusses the immunometabolic mechanisms underlying…

Chronic low-grade metabolic #inflammation drives insulin resistance and metabolic dysfunction in #obesity. Yun Sok Lee highlights the lesser known beneficial effects of this inflammation and how they can transition into detrimental outcomes. 🧪

Cerebral amyloid angiopathy and Alzheimer's and related pathologies across APOE genotypes Cerebral amyloid angiopathy is associated with age, APOE genotype, and Alzheimer’s disease pathology (AD). Mehta et al. now show that its severity is assoc

Cerebral amyloid angiopathy and Alzheimer's and related pathologies across APOE genotypes academic.oup.com/brain/advanc...

The Shingles vaccine has outperformed all expectations. Why?
erictopol.substack.com/p/spotlight-...

Peripheral cancer attenuates amyloid pathology in Alzheimer’s disease via cystatin-c activation of TREM2: @cellpress.bsky.social www.cell.com/cell/fulltex...

Go Sanders Brown and the Macauley Lab! So bummed to miss it!

Great study on @molneurodegen.bsky.social showcasing the differences of Aβ generated from glutamatergic and GABAergic neurons with distinct implications for plaque compaction, reactive gliosis, and axonal dystrophy!

link.springer.com/article/10.1...

I appreciated this. Dogma always suggests E3 is neutral, E4 is a risk allele, and E2 is protective. I like that this suggests that E3 carries its own risk. Unless I’m misinterpreting….

This ‘fundamental’ study uncovers how directing pyruvate into mitochondria can shrink cells by shifting their metabolism away from building amino acids and proteins.
buff.ly/hFHjKy9

Superiority of 1 h plasma glucose vs fasting plasma glucose, 2 h plasma glucose and HbA1c for the diagnosis of type 2 diabetes - Diabetologia Aims/hypothesis The IDF has proposed 1 h plasma glucose (1 h PG) as a diagnostic test for type 2 diabetes. This study evaluated the utility of 1 h PG in diagnosing type 2 diabetes, compared with fasti...

Rethinking diabetes diagnosis: a meta-analysis shows that 1 h plasma glucose is superior to FPG, 2 h plasma glucose, #HbA1c or FPG plus HbA1c for detecting #Type2Diabetes earlier, potentially improving prevention and care #DiabetesResearch link.springer.com/article/10.1... 🔓

I feel this 😂

LDHA induces beta cell dedifferentiation in diabetes through metabolic and epigenetic reprogramming - Diabetologia Aims/hypothesis Pancreatic beta cell dedifferentiation underlies the reversible reduction in beta cell mass and function in diabetes. Exploratory research into interventional targets and adjuvant ther...

Lactate dehydrogenase A (#LDHA)-driven metabolic and epigenetic reprogramming in beta cell dedifferentiation during diabetes development, identifying LDHA inhibition as a promising therapeutic target. #DiabetesResearch #Pancreatic-β-cell #Dedifferentiaton link.springer.com/article/10.1...

#ArtAdventCalendar, Day 14!

Another hometown fav.

Watercolor, Lobster Landing, Clinton, CT

This is so important in the context of Alzheimer’s. Many studies suggest MetS or diabetes is not associated with AD risk, however they fail to consider T2D is treated. This reinforces the idea that managing metabolic dysfunction has widespread improvement for many age related diseases.

a woman is jumping in the air while a man holds her hands up . ALT: a woman is jumping in the air while a man holds her hands up .

Paper accepted!!!!!!! Yahooooo!!!

#ArtAdventCalendar, Day 11!

Watercolor, Seashells, Hammonasset State Park, Madison, CT.

#ArtAdventCalendar, Day 11

Watercolor, seagull on channel marker, Clinton Harbor, Clinton CT

#ArtAdventCalendar, Day 10

Watercolor, alcohol inks, acrylics. Inspired by Ramon y Cajal and Greg Dunn’s work.

#ArtAdventCalendar Day 8!

Carolina chickadee, watercolor.