**Thanks**

*Neuroprotection - New Approaches and Prospects*

were inactivated in the presence of the dendrimers.

memory protection in AD transgenic animals.

multifunctional drug candidate against Alzheimer's disease.

biodegradation could be tuned for a particular dendrimer application.

**4. Conclusions and perspectives**

PBS-treated mice [22].

To understand a possible mechanism behind the memory rescue, the levels of pre- and postsynaptic markers in the brain of treated APP/PS1 mice were evaluated by Western blotting. Pre- and postsynaptic markers, such as drebrin and synaptophysin, play a crucial role in the synaptic plasticity and are downregulated in AD [53, 54]. Loss of synaptophysin correlates with cognitive impairments in AD patients and AD transgenic models [54, 55]; Psd95 knockout animals have impaired basal synaptic transmission and learning deficit [56]; transgenic animals lacking synaptophysin have reduced novel object recognition [57]. Importantly, it has been shown that loss of synaptophysin immunoreactivity precedes amyloid plaque formation [58, 59]. Preventive treatment of AD transgenic mice with G4 histidinemaltose PPI dendrimers prevented a decrease in synaptic proteins compared to

In contrast, G4 histidine-maltose PPI dendrimers did not change the level of these synaptic proteins in WT mice, indicating that, most likely, the level of their mRNA expression was not affected [22]. Thus it is reasonable to think that the increased levels of pre- and postsynaptic proteins are more likely an effect of reduced synaptic loss in the treated AD transgenic animals (**Figure 8**). Thus a possible mechanism of memory protection in APP/PS1 could be the synapses were shielded by the dendrimers from toxic Aβ oligomers or the toxicity of Aβ oligomers

Dendrimers, which represent a type of 3D polymers, have been in the spotlight for three decades in biomedical and pharmaceutical research, and their chemistry and synthesis are continuously progressing by efforts from many research groups and companies. Although there are still many unclear problems in AD, in this chapter, functionalization of dendrimers dedicated to the prevention of memory decline in AD pathogenesis has been discussed. Based on the reviewed literature, PPI dendrimers have been shown to be useful in the way of the surface functionalization, which tuned their biochemical properties. Strikingly, the effect of the surface functionalization with histidine and maltose magnified exponentially neuroprotective properties of PPI dendrimers, resulting in an unprecedented outcome, such as

In this chapter, I have analyzed the functionalization of PPI dendrimers, which tuned the intrinsic properties of PPI dendrimers and converted them into a multifunctional drug candidate against Alzheimer's disease. Modification of the dendrimer surface with maltose allowed dendrimers successfully to interfere with Aβ(1–42) by forming nontoxic hybrid glycofibrils. Modification of the dendrimer surface with histidine improved the ability of the dendrimers to cross the blood– brain barrier and resulted in synaptic protection. By reducing the level of soluble amyloid oligomers, on the one hand, and conferring synapse protection, on the other hand, the dendrimers were given multifunctionality against main features of AD, synaptic loss, and aggregation of Aβ. These observations, coming out of the studies on the interaction of dendrimers with amyloid peptides [18, 22, 28, 32, 42], carried out in vitro and in vivo, point toward a possible use of dendrimers (in particular functionalization of PPI dendrimers with histidine and maltose) as a

However, to find a successful drug against AD, other modifications of histidinemaltose PPI dendrimers might be required. For example, the ability to cross the blood-brain barrier, cell wall penetration, distribution in the specific tissue, and

**98**

I thank Dr. Stefan Broselid for fruitful discussions and editorial help.
