Disruption of the membraneless organelles may explain toxicity of tau aggregates.
In cell culture, neurons with the strongest expression of cell-cycle proteins survived best in the presence of Aβ oligomers, hinting at a protective effect.
Based on early stage trials, scientists said at AD/PD that light and sound can promote neuronal communication, calm immune cells, and slow brain atrophy. On cognitive outcomes, the jury is still out.
After news on “new data” they won’t see, three committee members penned an editorial laying out their argument against approval. The agency is expected to decide on the licensing application by June.
In therapy-like paradigm, suppressing ApoE4 in astrocytes toned down tauopathy. This assuaged microglia, neurodegeneration, and revived nest-building.
New research implicates IL-6 signaling and even Aβ42 itself as BACE targets, complicating efforts to resurrect BACE inhibitors at a low dose.
Data from Phase 3 trials of elenbecestat show no harm to cognition, leaving open a chance that the drugs could be used safely in the future.
The first whole-genome manipulation of protein expression in neurons by CRISPR reveals a deadly chain of events. Bad processing by lysosomes leads to build-up of lipids and iron. Oxidative stress revs up. Neurons die by ferroptosis.
Virtual Exhibit Hall
Alzforum encourages users to visit the Virtual Exhibit Hall, where companies showcase their newest initiatives, products, and services. We welcome F. Hoffmann-La Roche, joining our other exhibitors — Biogen, BioLegend, Abcam, BrainXell, and the Jackson Laboratory.
If enhancing cognition with light and sound seems futuristic, then welcome to the future. Or so some scientists say. Results from four early stage clinical studies on mild Alzheimer’s disease were presented at the virtual AD/PD 2021 conference. The studies used two related approaches to modulate brain waves. Both reportedly synchronized neural firing in the gamma frequency range, harmonized neuronal connections, shifted the brain’s cytokine profile, and slowed brain atrophy. Memory and functional measures gave mixed results.
ApoE4, the strongest genetic risk factor for late-onset AD, is known to exacerbate the havoc caused by tau pathology. Now, researchers report that removing ApoE4 only from astrocytes assuages neurodegeneration, tau pathology, and even keeps microglia from devouring synapses. The findings paint astrocytic ApoE as an orchestrator of neurodegeneration.
BACE Inhibition: Not Quite Dead, But Complicated
Research presented at the 2021 AD/PD conference provides a glimmer of hope for BACE inhibitor therapy. Full data from the terminated Phase 3 elenbecestat trials finds no cognitive deficit, demonstrating that this side effect can be avoided. Meanwhile, basic research turns up a new BACE1 substrate, Gp130, which may affect synaptic transmission through IL-6 signaling. Other evidence implicates BACE1 in degrading Ab42, as well as forming it, suggesting inhibitor dosing might have to balance these roles. Altogether, BACE experts still see a pathway for low-dose BACE inhibition as a preventative strategy. Read Madolyn Bowman Rogers’ Drop of Hope? No Cognitive Worsening on BACE Inhibitor and What BACE Hits: New Substrates Create New Headaches.
The first-ever genome-wide CRISPR screen in human neurons discovered that a toxic brew of lysosomal lipids, reactive iron atoms, and oxidative stress can spell doom for this cell type specifically. Researchers led by Martin Kampmann at the University of California, San Francisco, used the genome-editing tool to dial up or down expression of each protein-coding gene in the human neuronal genome. They uncovered a surprising connection between endolysosomal processing and the iron-dependent cell-death pathway called ferroptosis. In a separate CRISPR screen, the scientists implicated endosomal-transport genes—particularly the enzyme PIK-fyve—in α-synuclein aggregation.
Compared to non-Hispanic Caucasians, African Americans are more likely to carry TREM2 gene variants that curtail its expression, and are less likely to inherit a variant that enhances its processing. As a result, they have less soluble TREM2 in their cerebrospinal fluid. Understanding differences in TREM2 biology could be important when deciding cutoffs for diagnostic biomarkers or enrolling in clinical trials.
- Li-Huei Tsai on Does Synchronizing Brain Waves Bring Harmony?
- Peter Lansbury on Advisory Committee Again Urges FDA to Vote No on Aducanumab
- Shane Liddelow and Philip Hasel on Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
- Elena Galea on Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
- Sam Gandy and Michelle Ehrlich on Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
- Eileen Press on CD33M inhibits microglial phagocytosis, migration and proliferation, but the Alzheimer's disease-protective variant CD33m stimulates phagocytosis and proliferation, and inhibits adhesion.
- Jesse Hanson on Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
- Priyanka Narayan on Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
- John Fryer on Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration
- Robert Vassar on What BACE Hits: New Substrates Create New Headaches
- Robert Vassar on Drop of Hope? No Cognitive Worsening on BACE Inhibitor
- Stefan Lichtenthaler on Drop of Hope? No Cognitive Worsening on BACE Inhibitor
- Justin Ichida on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- Nathaniel Safren on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- William Hu on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- Jessica Young on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- Ellen Sidransky on Dysfunctional Lysosomes Cause Ferroptosis in Neurons
- Minerva Carrasquillo on TREM2 Variants and CSF sTREM2 Levels Differ by Race
- Arnon Rosenthal and Hervé Rhinn on TREM2 Variants and CSF sTREM2 Levels Differ by Race
- Mark Gluck on TREM2 Variants and CSF sTREM2 Levels Differ by Race
- William Hu on TREM2 Variants and CSF sTREM2 Levels Differ by Race