Protection Against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects

Abstract

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.

Microtubule stabilising peptides rescue tau phenotypes in-vivo

“…These peptides do not exhibit stereo-selectivity59. The more stable, all D-amino acid SAL (D-SAL) showed efficacy in-vivo and in-vitro models of disease3031. In a model of fetal alcohol syndrome (FAS), administration of both D-NAP and D-SAL reduced fetal demise, however, no significant differences between combination and individual drug treatments were seen.…”

“…SAL is derived from the glial precursor protein, activity dependent neurotrophic factor (ADNF). It exhibits similar neuroprotective capabilities to NAP in numerous animal and cell models of injury and disease2728293031.…”

Microtubule-Tau Interaction as a Therapeutic Target for Alzheimer’s Disease

“…Capitulating on the NAP target, we have designed SKIP (Ser-Lys-Ile-Pro) and shown that it mimics NAP protection, as well as protects ADNP-deficient impairment in axonal transport (Amram et al 2016). Together with new diagnostic tools, such as changes in blood ADNP in parallel to brain cognitive decline , this and other pipeline products (Shiryaev et al 2011;Gozes et al 2014a, b) are ready for future development, at the basic mechanistic understanding and at the clinical frontiers. …”

Neurotrophic Peptides: Potential Drugs for Treatment of Amyotrophic Lateral Sclerosis and Alzheimer’s disease

“…Other possible mechanisms of neuroprotection include the Bcl2 mitochondrial intrinsic signaling pathway, which regulates cell survival and apoptosis [70] and the extrinsic JNK signaling pathway [71]. The all D-amino acid analogue of ADNF-9 was found to protect against Aβ tau hyperphosphorylation, in early events, in vitro and in vivo, with regards to neuroprotection and maintenance of neuronal organization [72]. ADNF-9 was tested in in vitro and in vivo ALS models [58].…”