TAU researcher says discovery may lead to improved memory, cognitive function in Alzheimer’s patients.
Alzheimer’s disease progressively destroys neurons, particularly in the hippocampus and cortex, and with this loss comes reduced neuroplasticity—the brain’s ability to adapt, learn, and form memories. Preserving or restoring that plasticity is a promising strategy to slow cognitive decline and improve quality of life for people living with Alzheimer’s. New research from Tel Aviv University identifies a molecular target that helps protect nerve cells and sustain the dynamic properties of the brain.
The study, led by Prof. Illana Gozes of Tel Aviv University and published in Molecular Psychiatry, describes how a short peptide derived from the activity-dependent neuroprotective protein (ADNP) acts on microtubule regulatory machinery to support synaptic plasticity. According to Prof. Gozes, “This discovery offers a new target for drug design and clarifies molecular mechanisms of cognitive enhancement.”
Background and significance
Prof. Gozes’ earlier work identified NAP, a short peptide fragment of ADNP, as a neuroprotective molecule. ADNP is crucial for brain development, and its NAP motif has been developed into a drug candidate known as Davunetide (also referred to as NAP). Clinical trials and studies have suggested that Davunetide can protect memory in people with mild cognitive impairment (MCI), a condition that often precedes Alzheimer’s disease. The new study clarifies the peptide’s precise molecular action, strengthening the rationale for further clinical development.
How NAP stabilizes microtubules and supports plasticity
The core advance reported by the researchers is the identification of a mechanism by which the NAP motif enhances microtubule dynamics at their growing ends. Microtubules are filamentous structures inside cells that serve as structural supports and intracellular transport tracks. Neurons depend heavily on microtubules because they must extend materials along axons and dendrites to maintain synapses and cellular function. In many neurodegenerative conditions, including Alzheimer’s, the microtubule network becomes destabilized, compromising neuronal transport and synaptic health.
The investigators demonstrate that NAP binds to microtubule end-binding proteins (EB proteins) at the tips of growing microtubules. These EB proteins behave like molecular “locomotives,” attaching to microtubule plus-ends and recruiting regulatory factors that promote growth and remodeling. By interacting with EB proteins, NAP enhances the association of ADNP with microtubules, promoting microtubule stability at sites where new growth is occurring. This stabilization supports the formation and maintenance of dendritic spines—the small protrusions where synapses form—and therefore supports synaptic plasticity and neural resilience.
“We have shown that ADNP, via its NAP motif, binds microtubule end-binding proteins and enhances nerve cell plasticity, providing brain resilience,” Prof. Gozes explains. “We also found that NAP further strengthens ADNP’s binding to microtubules.”
Implications and next steps
Clarifying this molecular interaction offers a concrete target for therapeutic development: compounds that mimic or enhance the NAP–EB protein interaction could help stabilize neuronal microtubules and maintain synaptic function in aging and neurodegeneration. The authors hope these insights will accelerate additional clinical evaluation of Davunetide (NAP) and related compounds in conditions characterized by impaired neuroplasticity, such as MCI and Alzheimer’s disease.
Prof. Gozes and her team are continuing to study microtubule end-binding proteins and their role in protecting neurons, aiming to better define how modulation of these proteins can preserve cognitive function.
Prof. Illana Gozes holds the Lily and Avraham Gildor Chair for the Investigation of Growth Factors and directs the Adams Super Center for Brain Studies at Tel Aviv University’s Sackler Faculty of Medicine. She is also a member of TAU’s Sagol School of Neuroscience. Coauthors on the study include Dr. Saar Oz, Oxana Kapitansky, Yanina Ivashco-Pachima, Anna Malishkevich, Dr. Joel Hirsch, Dr. Rina Rosin-Arbesfeld and their students, all affiliated with Tel Aviv University. TAU staff scientists Dr. Eliezer Gildai and Dr. Leonid Mittelman contributed advanced molecular cloning and cellular protein imaging that supported the work.
Contact: George Hunka – American Friends of Tel Aviv University
Source: American Friends of Tel Aviv University press release
Image source: Credit to SilverGryphon8; image used for illustrative purposes.
Original research: “The NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins” by S. Oz et al., published in Molecular Psychiatry (2014). DOI: 10.1038/mp.2014.97