**3.2 New generation therapies**

*Neuroprotection - New Approaches and Prospects*

**Parkinson's diseases**

**3.1 Traditional ongoing therapies**

flexibility is responsible for its multifunctional properties, its capability to adopt different conformations, and to interact with different systems and other proteins [77]. For example, the interaction of Syn with negatively charged membranes, vesicles, bilayers, and lipids in general has important physiological consequences [78, 79], corroborating the hypothesis that Syn functions are correlated with lipids [80].

**3. Overview of recent therapeutic approaches in Alzheimer's and** 

Current pharmacological therapies (**Table 2**) for neurodegenerative diseases focus to ameliorate the life conditions of patients and are generally only palliative. Since in many cases, the aberrant deposition of the protein strongly contributes to the toxicity associated with the diseases, some treatments are currently thought to target such specific proteins (i.e., Syn and Aβ) in order to restore their correct physiological levels *in vivo.* Given the complexity in the onset and progression of these diseases, treatments should be customized and tailored to the individual needs of the patients. In the case of AD, a therapy based on the use of cholinesterase inhibitors (ChEIs) and the N-methyl-d-aspartate (NMDA) antagonist is currently available and Food and Drug Administration (FDA)-approved. In particular, three ChEIs are used: donepezil, rivastigmine, and galantamine [81]. The aim is to increase the levels of acetylcholine, a neurotransmitter responsible for memory and cognitive function, by reducing its enzymatic breakdown. Another class is represented by NMDA receptor antagonists, such as memantine, a noncompetitive antagonist, capable to block the effects of the excitatory neurotransmitter glutamate [82]. There are

**44**

**Table 2.**

*Current available drugs for the treatment of AD and PD.*

Novel experimental approaches are under investigation and the most promising have as a target the protein involved in the diseases. The stages of intervention could be at the level of the protein synthesis or clearance and at the level of protein aggregation or propagation of the toxic species or their precursors (**Figure 5**).

1.*Control of the protein concentration in vivo*. To reduce the production of Aβ, Tau, and Syn, the RNA interference approach is to date quite attractive [85–87]. It is based on the idea to inhibit specific protein expression by activating a sequence-specific RNA degradation process. This technology results useful to study gene function, investigate the mechanism of the disease, and validate drug targets. Of course, the suppression of the target protein might have

#### **Figure 5.**

*New generation therapies in AD and PD. Potential levels of intervention to counteract the abnormal accumulation of the amyloidogenic proteins and restore their physiological concentration, which results from a balance between the rates of synthesis, clearance, aggregation, and propagation.*

negative implications, due to the alteration of its physiological equilibrium. Additionally, the transcription of the gene can be reduced. Clenbuterol was shown to be efficient in reducing Syn expression by 35% in neuroblastoma cell lines [88]. Some AD therapies based on the modulation of AD gene expression are proposed on the basis of the important progresses made in the understanding of the transcriptional regulation of some enzymes such as beta-secretase 1 (BACE1), apolipoprotein E (apoE), APP amyloid precursor protein (APP), and presenilin (PSEN) promoters [89]. Alternatively, to reduce the level of the active protein *in vivo*, its clearance can be enhanced. This can be obtained by increasing the intracellular degradation *via* autophagy or *via* the ubiquitin system. This topic is excellently reviewed by Boland et al. [90].

2.*Protein aggregation inhibitors*. An attractive approach would be the use of small molecules able to bind the monomeric form of the protein preventing its assembly into potentially toxic aggregates. Unfortunately, it remains still unclear which conformation of these proteins must be targeted, since all of them are natively unfolded, and multiple and concurrent events contribute to their conversion in oligomers and fibrils [91]. In this ambit, the use of polyphenols is quite promising, and, as described below, these compounds exhibit in some cases the ability to disaggregate preformed oligomers and fibrils [92].
