In the prevention of neurodegeneration associated with aging and neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease), neuronal differentiation is of interest. In this context, neurotrophic factors are a family of peptides capable of promoting the growth, survival, and/or differentiation of both developing and immature neurons. In contrast to these peptidyl compounds, polyphenols are not degraded in the intestinal tract and are able to cross the blood–brain barrier. Consequently, they could potentially be used as therapeutic agents in neurodegenerative pathologies associated with neuronal loss, thus requiring the stimulation of neurogenesis. We therefore studied the ability to induce neuronal differentiation of two major polyphenols present in the Mediterranean diet: resveratrol (RSV), a major compound found in grapes and red wine, and apigenin (API), present in parsley, rosemary, olive oil, and honey. The effects of these compounds (RSV and API: 6.25–50 µM) were studied on murine neuro-2a (N2a) cells after 48 h of treatment without or with 10% fetal bovine serum (FBS). Retinoic acid (RA: 6.25–50 µM) was used as positive control. Neuronal differentiation was morphologically evaluated through the presence of dendrites and axons. Cell growth was determined by cell counting and cell viability by staining with fluorescein diacetate (FDA). Neuronal differentiation was more efficient in the absence of serum than with 10% FBS or 10% delipidized FBS. At concentrations inducing neuronal differentiation, no or slight cytotoxicity was observed with RSV and API, whereas RA was cytotoxic. Without FBS, RSV and API, as well as RA, trigger the neuronal differentiation of N2a cells via signaling pathways simultaneously involving protein kinase A (PKA)/phospholipase C (PLC)/protein kinase C (PKC) and MEK/ERK. With 10% FBS, RSV and RA induce neuronal differentiation via PLC/PKC and PKA/PLC/PKC, respectively. With 10% FBS, PKA and PLC/PKC as well as MEK/ERK signaling pathways were not activated in API-induced neuronal differentiation. In addition, the differentiating effects of RSV and API were not inhibited by cyclo[DLeu⁵] OP, an antagonist of octadecaneuropeptide (ODN) which is a neurotrophic factor. Moreover, RSV and API do not stimulate the expression of the diazepam-binding inhibitor (DBI), the precursor of ODN. Thus, RSV and API are able to induce neuronal differentiation, ODN and its receptor are not involved in this process, and the activation of the (PLC/PKC) signaling pathway is required, except with apigenin in the presence of 10% FBS. These data show that RSV and API are able to induce neuronal differentiation and therefore mimic neurotrophin activity. Thus, RSV and API could be of interest in regenerative medicine to favor neurogenesis.

Purpose: Dementia is a multifactorial idiopathic pathology caused by clinical, eDementia is a multifactorial idiopathic pathology caused by clinical, environmental and genetic factors. Hence, its etiology is still unknown. We aimed to evaluate the association between five genetic risk factors for vascular diseases and dementia individually and when gathered in haplotypes. Materials and Method: We enrolled 200 dementia patients and 300 controls. All subjects were genotyped for vascular diseaseassociated polymorphisms in the genes coding for Apolipoprotein-E (ApoE), angiotensin converting enzyme (ACE) and Paraoxonase-1 (PON1). Results: The association between dementia risk and all the studied polymorphisms except of PON1-Q192R was found to be significant. Carrying the ApoE e4 allele seems to increase dementia risk by 4.32 fold (p = 0.001). The risk associated with ACE I and PON1-L55M T alleles were lower (2.58 and 2.11 fold, p < 0.001 and p = 0.015, respectively). When combined in haplotypes, these polymorphisms showed a cumulative and synergetic effect. GTICC haplotype appears to be associated with 9-fold dementia risk (p < 0.001), whereas AADTT seems to reduce dementia risk by 80% (p = 0.003). Conclusion: Our results suggest that, ApoE ε4, ACE I and PON1-L55M T alleles are associated with dementia risk whether these polymorphisms were studied separately or gathered in haplotypes. Still, the contribution of each gene to the pathophysiological development of dementia must be more investigated.