A new crystal structure shows a unique shape of Aβ in the arms of solanezumab. Exactly how this and other antibodies in the clinical pipeline grip Aβ could explain some differences in trial results.
Cellular, animal, and human studies suggest that the AD risk gene PICALM escorts Aβ through the blood-brain barrier.
In separate studies, researchers propose that high CSF ferritin and D-serine could become biomarkers to predict declining cognition in Alzheimer’s disease.
They overexpress Activin, allowing neurons to regrow axons in the central nervous system.
The motor neurons most sensitive to ALS require a microRNA cluster to survive, lest PTEN activates apoptosis.
The signature fall of cerebrospinal fluid concentrations of Aβ that herald Alzheimer’s may be preceded by a brief boost.
A new screening method detects interactions with mutated proteins that cause neurodegenerative disease.
Two large studies measured the occurrence of amyloid pathology in people with AD and other dementias. They confirm that amyloid may precede dementia onset by more than two decades, and rises with age, particularly in people with the ApoE4 gene.
Whether an antibody against Aβ ultimately proves successful as a treatment for Alzheimer’s disease may come down to how exactly it grips the peptide. A new crystal structure reveals that solanezumab captures a conformation of Aβ that could represent an intermediary between a monomer and oligomer. The antibody crenezumab, which also binds the midsection of Aβ, may do much the same, whereas the N-terminal antibodies bapineuzumab, gantenerumab, and aducanumab recognize different structural epitopes. Some clinical trial results hint that efficacy and the severity of side effects may correlate with what conformation or epitope the antibody recognizes.
GWAS consistently link PICALM variants to Alzheimer’s, but how this endocytic protein affects risk is unclear. Previous work points to Aβ production, but new evidence highlights clearance of the peptide instead. In last week’s Nature Neuroscience, researchers report that PICALM is essential for internalizing Aβ and transporting it across endothelial cells to be dumped to the bloodstream. A common PICALM variant that lowers AD risk results in more PICALM expression and faster Aβ clearance.
A climb in CSF concentrations of Aβ40 and Aβ42 happens just as the first plaques seed the brain in three AD mouse models, according to a new study. Then, as plaques take hold, CSF concentrations dwindle. The initial blip in Aβ has been observed in humans as well, and researchers think it could signify a very early stage of the disease. However, using this as a predictive biomarker could prove tricky, as concentrations on the way up equal those on the way down.
Mutations that cause neurodegenerative disease have numerous effects on cells, but how can scientists track them down? A novel screen reveals that mutant and wild-type versions of five disease proteins differentially bind to dozens of other partners. The mutant proteins cause familial forms of Alzheimer’s, Parkinson’s, Huntington’s, and spinocerebellar ataxia. Their differential interactions may provide clues to disease mechanisms. For example, APPSwe preferentially bound LRPPRC, a protein that regulates mitochondrial genes.
Two meta-analyses offered up the most definitive data to date on the prevalence of amyloid in people without dementia, or with Alzheimer’s or another dementia. As judged by amyloid-PET scans or CSF Aβ42 levels, people with normal cognition are more likely to harbor amyloid as they get older, and the prevalence more than doubled in people carrying the ApoE4 gene. This confirms previous studies. Amyloid prevalence decreased with very old age in people clinically diagnosed with AD, hinting that other age-related pathologies are at play in old people. Those with most non-AD dementias had increasing rates of amyloid with age. The findings may help clinicians choose inclusion criteria for clinical trials, and improve diagnosis.
- Ronald DeMattos, Robert Dean and Eric Siemers on Shape of a Hug: How the Embrace of a Therapeutic Aβ Antibody Really Matters
- Taisuke Tomita on New Role For PICALM: Flushing Aβ From the Brain
- Amalia Cecilia Bruni, Maria Elena Conidi and Livia Bernardi on APP A713T
- Michael Costigan on Mouse Axons CAST Off Inhibitors for Stunning Regeneration
- Hugo Geerts on Computational Modeling—Will it Rescue AD Clinical Trials?
- Pieter Jelle Visser on Could New Fluid Biomarkers Refine Alzheimer’s Diagnosis?
- Steve Barger on d-serine levels in Alzheimer's disease: implications for novel biomarker development.