Activity-dependent neuroprotective
protein (ADNP) is essential for brain formation and partial deficiency in ADNP results in cognitive deficits coupled with
tauopathy and neuronal cell death. Our previous results indicated that a
peptide snippet from ADNP, NAPVSIPQ (NAP, generic name,
davunetide) can restore in part ADNP deficiencies. NAP interacts with
tubulin and this interaction is displaced by the NAP related
peptide that is derived from
activity-dependent neurotrophic factor (ADNF),
SALLRSIPA (SAL) and its all D-
amino acid peptide derivative (D-SAL, also known as AL-309). Both NAP and D-SAL were shown to protect neurons against
amyloid beta toxicity however the mechanism of protection is still under investigation. In addition, NAP protects against tau hyperphosphorylation associated with ADNP deficiency, in vivo. To investigate whether the mechanism of in vitro neuroprotection relates to the in vivo protection against
tauopathy and to draw potential additional parallelism between NAP and D-SAL, we asked if: 1]NAP and D-SAL protect against
amyloid beta related tau hyperphosphorylation in vitro; and 2] D-SAL protects against haploinsufficiency in ADNP, inhibiting
tauopathy in vivo. Assessment of NAP and D-SAL neuroprotection in primary cortical neuro-glial cultures treated with
amyloid beta showed that both
peptides reduced toxin-related neuronal damage and protected against tau hyperphosphorylation. In vivo, chronic D-SAL administration protected against tau hyperphosphorylation associated with ADNP deficiency (ADNP+/- mice), showing for the first time protection against deficits in odor discrimination and in social recognition. These studies associate neuroprotection in vivo and in vitro and provide a broad base for future
drug development based on NAP and D-SAL against multiple neurodegenerative conditions.