Good news! New drug development is too slow as this case exemplifies again! Hopefully, in the near future machine learning & AI will accelerate drug development!
"... That’s why a new study from Northwestern University offers so much hope, because if researchers there are correct, their new small-molecule NU-9 drug may be able to stop Alzheimer’s disease long before it begins ruining lives. ..."
"... An experimental drug developed at Northwestern University has demonstrated further promise as an early intervention for Alzheimer’s disease.
In a new study, Northwestern scientists identified a previously unknown highly toxic sub-species of amyloid beta oligomers — toxic clusters of peptides — that appear to drive several of the brain’s earliest changes, including neuronal dysfunction, inflammation and activation of immune cells.
The experimental drug, a small-molecule compound called NU-9, decreased this toxic amyloid beta oligomer subtype and dramatically reduced the damage it causes in a mouse model of Alzheimer’s disease. ..."
"... Conceived about 15 years ago, NU-9 emerged as part of Silverman’s multi-year effort to discover a small molecule compound that could prevent toxic protein aggregate buildup in neurodegenerative diseases. By 2021, NU-9 demonstrated efficacy in animal models of amyotrophic lateral sclerosis (ALS), clearing toxic SOD1 and TDP-43 proteins and restoring health to upper motor neurons. In 2024, it received clearance from the U.S. Food and Drug Administration to begin human clinical trials for ALS. ..."
From the abstract:
"INTRODUCTION
Neuronal degeneration and immune cell activation occur early in Alzheimer's disease (AD), but the responsible molecules remain undetermined. While exogenous amyloid beta oligomers (AβOs) induce neuronal death and gliosis, the role of endogenous AβOs is less defined.
METHODS
Brain sections from 1- to 12-month-old 5xFAD mice were immunolabeled for AβOs, activated glia, phosphorylated transactive response DNA-binding protein 43 kDa (pTDP-43), and other AD markers. Neuropathology was analyzed following 60-day oral treatment with NU-9, a small-molecule AβO inhibitor.
RESULTS
By 8 weeks, AβOs accumulated in the subiculum alongside early reactive astrocytes and activated microglia.
Clinical-stage antibody ACU193 detected AβOs in early-stage degenerating neurons, while NU4-labeled denser deposits in late-stage degenerating neurons. ACU193+ AβOs accumulated on reactive astrocyte surfaces, which also contained pTDP-43, and later emerged inside activated microglia.
NU-9 reduced astrocyte-associated ACU193+ AβOs, pTDP-43, and markedly diminished glial fibrillary acidic protein.
DISCUSSION
These findings demonstrate in vivo efficacy of NU-9 and support targeting ACU193+ AβOs to mitigate AD progression.
Highlights
- ACU193+ AβOs accumulated as puncta in neurons at an early stage of degeneration, while NU4+ AβOs appeared as dense deposits only in late-stage degenerating neurons.
- The onset and progression of ACU193+ AβOs paralleled activated microglia and reactive astrocytes.
- ACU193+ AβOs significantly increased on reactive astrocyte surfaces, as NU4+ AβOs accumulated in halos around Thio-S+ plaque cores.
- In older mice, the ACU193 signal decreased on astrocytes and was found inside activated microglia.
- Sixty-day oral NU-9 treatment significantly reduced astrocyte ACU193+ AβOs and markedly decreased reactive astrogliosis.
..."
NU-9 halts Alzheimer’s disease in animal model before symptoms begin (original news release) "Study uncovers a new Alzheimer’s trigger — and a way to stop it"
Identification of a glia-associated amyloid β oligomer subtype and the rescue from reactive astrogliosis by inhibitor NU-9 (open access)
Fig. 8 Oral treatment with NU-9 reduces astrocyte-associated ACU193+ amyloid beta oligomers and pTDP-43+ ubiquitinated aggregates, and rescues GFAP levels.
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