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Autophagic impairment in sleep–wake circuitry is linked to sleep loss at the early stages of Alzheimer’s disease - Molecular Neurodegeneration Background Proteostasis, in particular the impairment of autophagic activity, is linked to sleep dysregulation and is an early sign of dementias including Alzheimer’s disease (AD). This coupling of events may be a critical alteration driving proteinopathy and AD progression. In the present study, we investigated sleep–wake and memory regulating neurons for vulnerability to autophagic impediment, and related these findings to progression of the sleep and cognitive phenotype. Methods Using the double knock-in AD mouse model, AppNL−G−FxMAPT, we examined phenotypic and pathological alterations at several timepoints and compared to age-matched single knock-in MAPT mice. Spatial learning, memory and executive Function were investigated in the Barnes maze. Sleep was investigated by 24-h locomotor activity and EEG. Immunostaining for autophagic, neuronal and pathological markers was conducted in brain regions related to memory (hippocampus, prefrontal cortex, entorhinal cortex) and the sleep–wake cycle (hypothalamus, locus coeruleus). Hippocampal electrophysiological recordings were conducted to probe neuronal Function during object investigation. A 3-day sleep disruption was conducted in MAPT mice to investigate autophagic changes following sleep loss. Autophagy was activated in MAPT mice with trehalose to probe effects on sleep recovery. Results We identified that disrupted sleep occurred from early-stages in AppNL−G−FxMAPT mice, that sleep declined over age, and sleep deficits preceded cognitive impairments in late-stages. Cytoplasmic autophagic impediment in hypothalamic and locus coeruleus sleep–wake neurons occurred in early-stage AppNL−G−FxMAPT mice, prior to significant β-amyloid deposition in these regions, with a failure of lysosomal flux over disease progression. Autophagic changes in the hippocampus and cortex at early-stage were predominantly in processes and less frequently associated with the lysosome. Plaque-associated autophagic and lysosomal accumulations were frequent from the early-stage. Sex differences in the AD phenotype were prominent, including greater cognitive decline in males than females, linked to increased proteostasis burden in EC layer II neurons and hippocampal tau in the late-stage. Conversely, sleep impairments were more rapid in females including less REM sleep recovery than males, along with greater autophagic burden in hippocampal processes of female AppNL−G−FxMAPT mice. We probed the sleep-cognition linkage demonstrating hippocampal electrophysiological slowing during cognitive processing in mid-stage AppNL−G−FxMAPT mice, prior to cognitive decline. We provide evidence for a positive feedback loop in the autophagic-sleep relationship by demonstrating that disrupted sleep in MAPT mice led to arrhythmic sleep patterns and accumulations of autophagic aggregates in the hippocampus and hypothalamus, similar to as was seen in the early Alzheimer’s phenotype. We further probed the autophagy-sleep linkage by treating MAPT mice with trehalose to activate autophagy and demonstrate an improvement in sleep recovery following a sleep disruption. Conclusions These findings demonstrate the vulnerability of sleep-regulating neurons to proteostatic dysfunction and the sleep-autophagy linkage as an early, and treatable, Alzheimer’s disease mechanism. Graphical Abstract Morrone et al provide evidence for the linkage between sleep and autophagic disruptions in Alzheimer’s disease (AD) progression. At early AD stages, sleep-wake regulating neurons in the hypothalamus and locus coeruleus exhibit increased cytoplasmic inclusions concomitant with the onset of sleep disturbances. Early-stage autophagic aggregates in the hippocampus appear more prominently in neuronal processes and in the cortex linked to plaques. This pathology worsens over AD progression, including advanced sleep and cognitive deficits, autophagic aggregates in entorhinal cortex-hippocampus projecting neurons. Disrupting sleep in control mice mimics the hippocampal, hypothalamic and sleep patterns impairments observed in early-stage AD, and therapeutic activation of autophagy improves sleep recovery. See also Table 1 for a summary of changes along with sex differences in autophagy and behavioral readouts.

Happy to announce the @YuTorontoLab's (@PharmTox_UofT) latest paper, published in @MolNeuro #sleep #proteostasis #autophagy #openaccess
molecularneurodegeneration.biomedcentral.com/articles/10....

'Don't be a pushover': Passenger rights activist on what you need to know before possible Air Canada strike "Keep all documents, keep recordings, audio, video," said Gábor Lukács. "And don't be a pushover."

'Don't be a pushover': Passenger rights activist on what you need to know before possible Air Canada strike

nationalpost.com/news/canada/...

Dr. Maria Carillo, always inspiring, always championing Alzheimer’s research, medicine and care, speaking to a packed room and the 11000 attendees of the @alzassociation.bsky.social #AAIC25 conference

Dr. Joanne Pike, CEO and President of @alzheimerssoc.bsky.social kicking off #AAIC25, inspiring and calling for continued support and advocacy, to ensure research endures and thrives globally!

Attending @AAIC25 in Toronto? Come visit the Yu Lab presentations. We have posters from both the preclinical research and the US-Canada wide NIH funded @ACADstudy work. In addition, I will give the opening talk at AAIC for all (July 31st). This is a free event open to the public! QR code in image!

Summer celebration for the YuToronto Lab. We have a new grant, new fellowship (Darcy) and new paper accepted (Chris). Not to mention a fabulous undergrad summer student from abroad (Jolin) and a dynamic team of clinical researchers for our @ACADstudy team.

Summer celebration for the YuToronto Lab. We have a new grant, new fellowship (Darcy) and new paper accepted (Chris). Not to mention a fabulous undergrad summer student from abroad (Jolin) and a dynamic team of clinical researchers!

NIH staff are being required to fully fund ~ 50% of their grants. This means that all 4 years of an award will be paid out of this appropriation. This will help them get the appropriated funds spent, but will mean they can only fund (1/2 + 1/4*1/2) = 5/8 has many grants as they would have otherwise.

The 3-decade-old competition that enabled the emergence and evaluate of AlphaFold has run out of NIH funding.

The program will be terminated in weeks.

This is terminating success.

www.science.org/content/arti...

The Alzheimer's Association International Conference is holding a hybrid event for everyone (AAIC-for-All) on July 31st from 9am-1pm (EST). I will be kicking it off and hope you can join. More info can be found here (and to register) - www.alz.org/aaic-for-all...

Please share!

a man in a suit and tie is smoking a cigarette and saying `` we will not go quietly into the night '' . ALT: a man in a suit and tie is smoking a cigarette and saying `` we will not go quietly into the night '' .

The clock starts now to try and prevent the massive cuts proposed for NIH, NSF, etc in the appropriations bill. I don’t have any brilliant ideas, but I’m hopeful that the people I’ve seen on here organizing and advocating and speaking out can take it to the next level for this new fight.

The 2026 health and health care budget | Brookings Richard Frank analyzes the administration's first 2026 budget and its impacts on health and health care policy and funding.

A jarring review of the NIH cuts in the budget bill that just passed the Senate. www.brookings.edu/articles/the... $48B -> 27.5B (40% cut). 19 Institutes -> 8, NIMHD eliminated! NCI grants reduced by 38.6%, Alz research grants by 45.5%. F&A dropped to 15%. Effectively gutting research!

Amplifying this message in the hopes the larger Bluesky community takes notice and can help out. As you know, research is being challenged on many fronts. Already approved grants are being withheld and it is hurting progress. Please support science if you can. @talnuriel.bsky.social is one example!

But I do think the priority right now is getting NIH to release our funds. As much as I’d love for us scientists to be able to replace that money with direct donations, I don’t think it’s a reality. I’m gonna keep trying though.

Very sorry to hear, Tal! Let me know if there’s anything I can do and hopefully the funds held up are released soon! Scientific research is being used as a pawn in a political fight and medical research like yours can only benefit society. Shame people are not seeing this is a needed investment.

Devastating cuts!

Four charts showing the extent of cuts to NASA in the FY26 budget:

- Cuts to every science division
- Smallest science funding since 1984
- 19 active, inflight missions cancelled
- Smallest NASA budget since FY 1961

The plan for NIH is in, source with full 64 page proposal for all of HHS is linked. Reported in WaPo. This is catastrophic. Reduction to 8 centers. 40% cut in budget. 15% IDC cap. This will decimate science across America open.substack.com/pub/insideme...

Applications open until April 1st for this course - please share far & wide!

This does not include long term gains that include training of new professionals, groundwork for new technology, seeds for new startups and biotechs and long-term diagnosis, treatments and cures. NIH is a necessary part of a thriving economy and for medical advancement! 2/2

United For Medical Research UMR is a coalition of leading research institutions, patient and health advocates and private industry seeking steady and sustainable increases in funding for the National Institutes of Health (NIH) i...

United for Medical Research released their 2024 report on the economic impact of NIH funding. $36.9B extramular funding resulted in $94.6B in local economies across the USA. This is an immediate 2.56X return on investment.
www.unitedformedicalresearch.org 1/2

Devastating (and probably illegal) actions by NIH. Let's gut scientists careers and stop the advancement of medical research! 🤦‍♂️ 🤯

I am able to get back on after clearing my cache. I also was able to get on with another browser

Pubmed and other NIH site users - see if clearing your cache helps. I am able to get back into those portals after clearing my temporary cache file

Yes, great alternative given uncertainty of Pubmed. I posted elsewhere but forgot to add to this thread.
I have also asked Endnote how to import from PMC Europe (think you can on Zotero).

and directly contacting Reps and Senators - www.house.gov/representa..... www.senate.gov/senators/sen...

Everything NIH has been down since yesterday - PUBMED CommonsPlus. RePORTER. I think there were reports the DNS is off line. If so, only an authenticated Superuser Administrator has privilege to reset.

The destruction is happening at break neck speeds and may affect a generation of scientists and budding scientists who will turn away. But this is also a call to voters - elections have consequences, scientists and their supporters need to support science. The need to be heard and contact Reps/Sens!

Yes, actually all of NIH portals are down for the last day. Europe PMC is still working if you need to search references. It doesn't port to Endnote, but think it works with Zotero.

“Reporter” is being generous when referring to the questionner’s profession