The 8-amino-acid neuroprotective peptide NAP, delivered intranasally as AL-108, improved memory in early Alzheimer's patients in a Phase IIa trial by targeting tau tangle formation through microtubule stabilization.
8 amino acids, delivered through the noseNAP (NAPVSIPQ) is one of the smallest neuroprotective peptides to reach clinical trials, delivered intranasally to bypass the blood-brain barrier and stabilize neuronal microtubules
What the researchers found
NAP (NAPVSIPQ), an 8-amino-acid neuroprotective peptide delivered intranasally as AL-108, showed positive results on memory function in a Phase IIa clinical trial for patients with amnestic mild cognitive impairment (aMCI), a precursor to Alzheimer's disease. NAP works by stabilizing microtubules — the internal structural scaffolding of neurons — against tau-related damage that causes neurofibrillary tangles, one of the hallmarks of Alzheimer's. This was one of the first tau-targeted peptide approaches to reach clinical testing.
Why it matters
While most Alzheimer's drug development has focused on amyloid plaques, this peptide targets the other hallmark of the disease: tau tangles. NAP/AL-108 represented a novel approach — a small peptide that could be delivered through the nose to bypass the blood-brain barrier and protect neurons by stabilizing their internal architecture. The positive Phase IIa results suggested this tau-directed peptide strategy had clinical potential.
The numbers in context
NAP: 8 amino acids (NAPVSIPQ) · Delivery: intranasal (AL-108) · Phase IIa: positive memory effects · Target: microtubule stability / tau tangles · Population: amnestic MCI patients
How the study worked
Review of NAP's discovery, preclinical pharmacology (in vitro and in vivo neuroprotection studies), mechanism of action (microtubule stabilization), and Phase IIa clinical trial results in amnestic mild cognitive impairment.
Who was studied
Patients with amnestic mild cognitive impairment (aMCI), a clinical precursor to Alzheimer's disease
What this study cannot tell us
Phase IIa is a small, early clinical trial — positive signals need confirmation in larger Phase II/III trials. The review is authored by the drug's developers, which introduces potential bias. Intranasal delivery of peptides to the brain remains technically challenging with variable absorption.
How to read the evidence
This review covers extensive preclinical data and a positive Phase IIa clinical trial, representing moderate evidence. Phase IIa trials are small and exploratory, and the review is authored by the drug's developers. Later clinical development of this peptide was not successful in a different indication.
When this study was published
Published in 2009, this review captures NAP/davunetide at its most promising clinical stage. The peptide subsequently failed a Phase II/III trial for progressive supranuclear palsy in 2012, and clinical development was discontinued. The underlying science of microtubule stabilization remains relevant to neurodegeneration research.
The bigger picture
NAP/davunetide was one of the pioneering peptide-based approaches to Alzheimer's that targeted tau pathology rather than amyloid. While later clinical development of davunetide did not succeed (a Phase II/III trial in progressive supranuclear palsy failed in 2012), the concept of tau-targeted neuroprotective peptides remains relevant. The approach also demonstrated the feasibility of intranasal peptide delivery to the brain, a route now being explored for many other neuropeptide therapeutics.
Questions still open
- Why did davunetide show promise in early Alzheimer's but fail in progressive supranuclear palsy — are these tau pathologies fundamentally different?
- Could modified versions of NAP with improved brain bioavailability revive the microtubule stabilization approach to tau-related neurodegeneration?
- How reliable is intranasal delivery for achieving consistent brain levels of therapeutic peptides?
Common questions
What are tau tangles and why do they matter in Alzheimer's?
Did this peptide drug ever make it to market?
Read the original research
Addressing Alzheimer's disease tangles: from NAP to AL-108.
Current Alzheimer research, 6(5), 455-60
Citation
Gozes, Illana; Stewart, Alistair; Morimoto, Bruce; Fox, Anthony; Sutherland, Karole; Schmeche, Donald. (2009). Addressing Alzheimer's disease tangles: from NAP to AL-108.. Current Alzheimer research, 6(5), 455-60.