Are Disease Mutations Lurking Within ‘Dark Regions’ of the Genome?
Thousands of stretches of the genome go undetected by standard short-read sequencing techniques. Unmasking these “dark regions” revealed a potential AD risk variant in the CR1 gene.
NEWS
When it Comes to Alzheimer’s Disease, Do Human Microglia Even Give a DAM?
Using single-nuclei or cell sorting, three separate research groups sequenced RNA from human postmortem brains. They unveiled AD-associated gene-expression signatures, but disease-related transcriptomes from human microglia were quite different from those in mice.
Antisense Oligonucleotides: Can They Take on ALS, SMA, Prions?
Data on ASOs, presented recently at the annual meeting of the American Academy of Neurology, depict RNA-based therapies as broadly on the rise in neurodegenerative diseases.
C9ORF72 Toxicity Tied to Mitochondria, Transcriptional Machinery
In a new, inducible mouse model, poly(GR) damages mitochondria, but its effect is reversible. In flies, turning off transcription of hexanucleotide expansion protects cells.
Paper Alert: VCAM1 Opens the Door to Brain Aging
Expression of VCAM1 on the endothelial cells that line the blood-brain barrier allowed aging factors in the plasma to exact their toll on the brain.
BACE Inhibitors: Postmortem on One, Live Updates on Two
Lanabecestat, elenbecestat, and umibecestat all showed data at the AD/PD conference in Lisbon. Learn what definitely doesn’t work and what might yet.
Plasticity Hums With Protein Synthesis on Both Sides of Synapse
Long recognized in dendrites, scientists now report that substantial synaptic proteome remodeling happens on the axonal side, too.
Gamma Waves Synchronized by Light: Good for Synapses, Memory?
More mouse data add to the argument that a flashing light sequence could potentially fight cognitive decline.
Virtual Exhibit Hall
Alzforum encourages users to visit the Virtual Exhibit Hall, where companies showcase their newest initiatives, products, and services. We welcome Dash Genomics, Inc. and Abcam, which join our other exhibitors — Biogen, BioLegend, BrainXell, NanoString Technologies, and the Jackson Laboratory.
SPOTLIGHT
DAM, PAM, HAM? What’s Going on in Alzheimer’s Brain?
Myriad studies place microglia front and center in AD pathogenesis, yet figuring out exactly what the immune cells are doing in the AD brain is a tall order. Three recent studies have taken a stab at uncovering transcriptomic signatures of microglia in postmortem AD brain samples, reporting that transcriptomes of human Alzheimer’s microglia (HAM) bear little resemblance to disease-associated microglia (DAM) of mouse models. Despite differences, some important similarities emerged, including a rise in ApoE and age-associated genes.
C9ORF72 Toxicity Tied to Mitochondria, Transcriptional Machinery
Two studies uncover new players in C9ORF72 toxicity, and suggest ways to shut them down. Scientists know that the most common genetic cause of ALS and FTD, C9ORF72 hexanucleotide repeats, generate toxic RNAs and a raft of dangerous dipeptides. Now a mouse model reveals that, even at low levels, the poly(GR) dipeptide poisons mitochondria, but the damage is reversible when caught early. The second study sheds new light on the specialized transcription machinery cells use to generate RNA from the repeat, suggesting new targets to choke off production at its roots.
AD/PD Coverage Closes With Two Updates on Anti-Amyloid Trials
We have concluded coverage from the 14th AD/PD conference held earlier this spring in Lisbon, Portugal. Our 16-part series runs the gamut from genetics to innate immune cells, from ApoE to lipids, from the search for diagnostic tests to the basic science of endocytosis and α-synuclein. We covered the pursuit of new therapeutic targets, as well as the painful harvest currently being reaped from Phase 3 anti-amyloid trials. On that, scientists at different companies were sharing detailed results from each other’s programs in hopes of learning as they "fall forward toward success." Crenezumab, lanabecestat, aducanumab are the latest official casualties; AD/PD offered data on the first two. Despite obituaries in the analyst press, the amyloid hypothesis is not dead. Gantenerumab, BAN2401, elenbecestat, umibecestat, and CAD106 are in late-stage trials, and crenezumab and solanezumab are still being evaluated in presymptomatic AD. See AD/PD Parts 15, 16.
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