Tau-targeting membrane-permeable peptides could slow Alzheimer’s disease
New membrane-permeable synthetic peptides could slow the progression of Alzheimer’s disease (AD) and other tauopathies. These new peptides inhibit tau phosphorylation by targeting specific and multiple phosphorylation sites. This halts disease progression by inhibiting tau mislocalization to dendritic spines and subsequent tau-mediated neural deficits. The technology is anticipated to treat Alzheimer’s disease and other tau-associated neurodegenerative conditions (e.g., frontotemporal dementia, traumatic brain injury, chronic traumatic encephalopathy).
Prevents tau hyperphosphorylation
Alzheimer’s disease (AD) has two main pathological hallmarks: beta-amyloid (Aβ) forming plaques and neurofibrillary tangles containing phosphorylated tau protein. No therapeutics currently exist that can slow or stop AD progression. Hyperphosphorylation of tau is associated with AD and other neurodegenerative diseases. Preventing hyperphosphorylation has become a key strategy. Previous attempts to treat AD by blocking tau phosphorylation failed because inhibiting the kinases (including CDK5 and GSK3) also shuts down other necessary cellular processes, leading to high toxicity. These two new peptides (termed WT and AP) prevent tau hyperphosphorylation. They act as targets for kinases so they do not hyperphosphorylate the tau protein. The WT peptide acts as a competitive inhibitor for the two kinases; the peptide becomes phosphorylated and native tau is not hyperphosphorylated. The AP modified peptide is unable to be phosphorylated but instead binds with the kinases, essentially “distracting” the kinases from native tau by so they phosphorylate native tau to a lesser extent. Because the peptides do not affect the global kinase activities of CDK5 and GSK3, they are likely to be highly effective without high toxicity.
Phase of Development
- In vitro proof of concept. Two synthetic peptides synthesized. One peptide inhibits tau phosphorylation in vitro. The other peptide localizes to neuronal dendritic spines in situ.
- Expected to slow progression of Alzheimer’s disease (AD) and other tauopathies
- Potential treatment for Alzheimer’s disease
- Does not affect global kinase activities of CDK5 and GSK3
- New membrane-permeable synthetic peptides
- Prevents tau hyperphosphorylation
- Prevents the tau mislocalization to dendritic spines that allows neurofibrillary tangles to form
- WT peptide acts as a competitive inhibitor of CDK5 and GSK3 kinases
- AP modified peptide binds with the kinases so they phosphorylate native tau to a lesser extent
- Alzheimer's disease
- Tauopathies and/or tau-associated diseases (Alzheimer's disease, fronto-temporal dementia, traumatic brain injury, chronic traumatic encephalopathy)
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