NAP, an octapeptide derived from activity-dependent neuroprotective protein (ADNP), reduces amyloid-β accumulation and tau hyperphosphorylation when given to mice intranasally, according to data published in the current issue of Journal of Molecular Neuroscience. The journal is edited by Illana Gozes, who discovered NAP. Continuing prior work on NAP (see ARF related news story), Yasuji Matsuoka of Georgetown University, Washington, and colleagues tested the peptide in triple-transgenic mice developed at Frank LaFerla’s lab at the University of California. Previously, coauthor Gozes showed that the peptide is neuroprotective in a variety of cellular AD models, but these are the first data that the peptide may protect against AD-like pathology in vivo. The finding provides support for clinical testing of NAP in AD patients, which is currently being pursued by Allon Therapeutics, Inc., a Canadian biotechnology company co-founded by Gozes and coauthor Paul Aisen of Georgetown University.

The triple-transgenic (3xTg-AD) mice express human APP, tau, and presenilin that all harbor disease-causing mutations (Swedish, P301L, and M146V mutations, respectively; see ARF related news story). Matsuoka and colleagues began treating the triple-transgenic mice with NAP when they reached 9 months of age, about the time when amyloid and tau pathology begins to develop. They gave the mice 0.5 micrograms of the peptide every weekday for 3 months, then measured Aβ load and tau phosphorylation status. They found that, compared to untreated 3xTg mice, NAP-treated animals had small, though significant reductions of about 20 percent in formic acid-soluble Aβ40 and Aβ42. The peptide had a larger effect on tau, reducing phosphorylation at serine 202/threonine 206 and threonine 231 by about 35 and 40 percent, respectively. The researchers did not report whether the treatment had any effect on the previously characterized learning and memory deficits in this model.

“I think that intranasal NAP has a robust effect on tau phosphorylation in the triple-transgenic model, and we will continue to pursue this in the lab,” said Paul Aisen, Georgetown University, in an interview with ARF. “The results are encouraging and suggest that the neuroprotective effect of NAP may be applicable to Alzheimer’s disease,” he added. NAP has been shown to stabilize microtubules, which may relate to its effects on tau phosphorylation. Modification of tau, particularly at threonine 231, weakens its affinity for microtubule binding and contributes to their destabilization.

Aisen told ARF that he has submitted a grant application to pursue an AD clinical trial with NAP. Allon Therapeutics, Inc., has conducted phase 1 safety trials of their intranasal preparation, AL-108, in patients with mild cognitive impairment, AD, and schizophrenia, and there is currently an NIMH-funded trial underway to assess the efficacy of AL-108 in treating schizophrenia-associated cognitive impairment, Aisen added. A phase 2 trial for MCI is currently recruiting patients (see ClinicalTrials.gov). An intravenous preparation is also being tested for cognitive impairment associated with coronary artery bypass surgery.—Tom Fagan

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References

News Citations

  1. Stockholm: Could a Whiff of NAP Nip Brain Inflammation in the Bud?
  2. San Diego: Treating Forgetfulness—Triple Transgenics Provoke

External Citations

  1. ClinicalTrials.gov

Further Reading

Primary Papers

  1. . Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer's disease at early pathological stage. J Mol Neurosci. 2007;31(2):165-70. PubMed.