**1. Introduction**

Alzheimer's disease (AD) is a complex neurological disease, which already in its earliest clinical phase is characterized by remarkable memory impairment. Multiple pieces of evidence suggest that in AD, memory impairment begins with dysfunction of synapses, a unique characteristic of nerve cells. Early neurochemical analyses of AD brain tissue revealed that the deficits in numerous neurotransmitters (including corticotropin-releasing factor, somatostatin, GABA, and serotonin) and the early symptoms correlate with dysfunction of cholinergic and glutamatergic synapses [1]. In addition to the deficits of the transmitters, many other biochemical and morphological indicators suggest that in early AD, synapses are under attack as reviewed in [2]. It has been shown that in biopsied AD cortex, there is a significant decrease in the numerical density of synapses in the brain and the number of synapses per cortical neuron [3]. The amyloid cascade hypothesis, one of the widely accepted theories, suggests that progressive accumulation and aggregation of amyloid-β proteins (Aβ) could be the main cause of AD, which triggers AD neuropathology. Aβ proteins are the proteolytic products of amyloid precursor protein (APP),

a type-I transmembrane protein which is highly expressed in neurons, known to regulate synaptic function and neurite outgrowth [4]. There are two main alternative enzymatic pathways to process APP [5]:


APP processing is regulated by neuronal activity, and neuronal activity may favor β-secretase-mediated amyloidogenic cleavage of APP during which Aβ proteins are generated [7]. It was accepted that after APP cleavage, Aβ peptides are first secreted, and then, extracellularly, soluble Aβ peptides aggregate into amyloid plaques. This extracellular Aβ, which is the main constituent of amyloid plaques, is thought to be toxic to the neurons. More recently, the intraneuronal Aβ has been demonstrated and reported to be involved in neuronal damage [8, 9]. It has been demonstrated that Aβ attacks synapses, small membranous protrusions that permit one neuron to pass a signal (electrical or chemical) to another neuron.

It has been shown that synaptic activity may affect Aβ secretion [5], and it has been hypothesized that synaptic activity may stimulate the generation of Aβ although why this occurs and whether Aβ might have a normal function in neuronal synapse have not been understood well [10]. Strikingly, it has been shown that Aβ selectively binds to synapses when added to cultured neurons [11]. Further, the level of Aβ is shown to be increased in synaptosomes in early AD [12]. Immunoelectron microscopy and high-resolution immunofluorescence microscopy studies show that this early subcellular Aβ accumulation leads to progressive damage of neurites and synapses [13]. Thus, synapses could be sites of early accumulation of pathogenic Aβ. It is believed that soluble Aβ oligomers rather than monomeric or fibrillar Aβ are the main neurotoxic species. However, a structure of neurotoxic Aβ oligomers and the nature of their effects on synapses are not identified [14].

Despite advances, the efforts to target neurotoxic Aβ oligomers in the brain are confounded by high polymorphism of amyloid structures [15]. Oligomer specific antibodies may interact mainly with a specific type of Aβ conformers against which these antibodies were produced [16]. Therefore, to target polymorphic Aβ oligomers, a cocktail from several antibodies might be required. Another way to modulate Aβ aggregation could be via establishing H-bond interactions [17] to favor the formation of less toxic Aβ species [18].

To fight a brain disease such as AD pathology, both synapse protection and anti-amyloid modulation would be desired properties of a possible therapeutic drug. However, to protect synapses and to modulate Aβ aggregation, amyloid aggregation modulator and neuroprotective therapeutics have to be delivered to the synapse. One way to deliver both therapeutic molecules is to use a compound which may carry both molecules simultaneously. Such multifunctional compound could be a dendrimer.

Dendrimers are three-dimensionally branched, globular macromolecules built by a series of iterative steps from a small core molecule which defines the type of the dendrimer [19]. They were first synthesized and described in 1978 [20], and since then dendrimers are in focus, due to their outstanding complexation properties. The most important features of dendrimers are controlled molecular structure, nanoscopic size, and high tunable availability of multiple functional groups at the dendrimer surface. Dendrimers are composed of three elements: a core branched

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**Figure 1.**

*dendrimers; circle 3 shows the terminal groups, R1*

*G4 histidine-maltose PPI dendrimers first with histidine (R1*

*Glycodendrimers as Potential Multitalented Therapeutics in Alzheimer's Disease*

dendron and terminal groups which could be used for dendrimer functionalization. The number of surface functional groups of the dendrimer depends on the degree of dendrimer branching (**Figure 1**). For example, PPI or PAMAM dendrimers of the

*Structure and chemical modification of dendrimers. (A) Molecular structure of poly(propylene imine) dendrimers of the fourth generation. Circle 1 shows the core; circle 2 indicates branching points of the* 

*histidine and maltose neutralizes the positive charge of the primary amino groups [22].*

 *and R2*

*Netherlands) was renamed as fourth-generation (G4) PPI dendrimers following the uniform nomenclature [21]. (B) Example of surface modification of the PPI dendrimer. A reaction pathway shows the synthesis of* 

*. Fifth-generation PPI dendrimer (Eindhoven, the* 

*). Conjugation with* 

*) and then with maltose (R2*

*DOI: http://dx.doi.org/10.5772/intechopen.88974*

*Glycodendrimers as Potential Multitalented Therapeutics in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.88974*

#### **Figure 1.**

*Neuroprotection - New Approaches and Prospects*

tive enzymatic pathways to process APP [5]:

oligomers, and fibrils [6]

a type-I transmembrane protein which is highly expressed in neurons, known to regulate synaptic function and neurite outgrowth [4]. There are two main alterna-

1.Non-amyloidogenic pathway, where APP is subjected to consecutive cleavage

2.Amyloidogenic APP pathway, where APP is subjected to cleavage by β-and γ-secretases generating Aβ, a mix of short peptides ranging from 38 to 43 amino acids in length able to form polymorphous aggregates, so-called

APP processing is regulated by neuronal activity, and neuronal activity may favor β-secretase-mediated amyloidogenic cleavage of APP during which Aβ proteins are generated [7]. It was accepted that after APP cleavage, Aβ peptides are first secreted, and then, extracellularly, soluble Aβ peptides aggregate into amyloid plaques. This extracellular Aβ, which is the main constituent of amyloid plaques, is thought to be toxic to the neurons. More recently, the intraneuronal Aβ has been demonstrated and reported to be involved in neuronal damage [8, 9]. It has been demonstrated that Aβ attacks synapses, small membranous protrusions that permit

by α-and γ-secretases that cut APP within the Aβ fragment

one neuron to pass a signal (electrical or chemical) to another neuron.

nature of their effects on synapses are not identified [14].

the formation of less toxic Aβ species [18].

It has been shown that synaptic activity may affect Aβ secretion [5], and it has been hypothesized that synaptic activity may stimulate the generation of Aβ although why this occurs and whether Aβ might have a normal function in neuronal synapse have not been understood well [10]. Strikingly, it has been shown that Aβ selectively binds to synapses when added to cultured neurons [11]. Further, the level of Aβ is shown to be increased in synaptosomes in early AD [12]. Immunoelectron microscopy and high-resolution immunofluorescence microscopy studies show that this early subcellular Aβ accumulation leads to progressive damage of neurites and synapses [13]. Thus, synapses could be sites of early accumulation of pathogenic Aβ. It is believed that soluble Aβ oligomers rather than monomeric or fibrillar Aβ are the main neurotoxic species. However, a structure of neurotoxic Aβ oligomers and the

Despite advances, the efforts to target neurotoxic Aβ oligomers in the brain are confounded by high polymorphism of amyloid structures [15]. Oligomer specific antibodies may interact mainly with a specific type of Aβ conformers against which these antibodies were produced [16]. Therefore, to target polymorphic Aβ oligomers, a cocktail from several antibodies might be required. Another way to modulate Aβ aggregation could be via establishing H-bond interactions [17] to favor

To fight a brain disease such as AD pathology, both synapse protection and anti-amyloid modulation would be desired properties of a possible therapeutic drug. However, to protect synapses and to modulate Aβ aggregation, amyloid aggregation modulator and neuroprotective therapeutics have to be delivered to the synapse. One way to deliver both therapeutic molecules is to use a compound which may carry both molecules simultaneously. Such multifunctional compound could be a dendrimer. Dendrimers are three-dimensionally branched, globular macromolecules built by a series of iterative steps from a small core molecule which defines the type of the dendrimer [19]. They were first synthesized and described in 1978 [20], and since then dendrimers are in focus, due to their outstanding complexation properties. The most important features of dendrimers are controlled molecular structure, nanoscopic size, and high tunable availability of multiple functional groups at the dendrimer surface. Dendrimers are composed of three elements: a core branched

**90**

*Structure and chemical modification of dendrimers. (A) Molecular structure of poly(propylene imine) dendrimers of the fourth generation. Circle 1 shows the core; circle 2 indicates branching points of the dendrimers; circle 3 shows the terminal groups, R<sup>1</sup> and R2 . Fifth-generation PPI dendrimer (Eindhoven, the Netherlands) was renamed as fourth-generation (G4) PPI dendrimers following the uniform nomenclature [21]. (B) Example of surface modification of the PPI dendrimer. A reaction pathway shows the synthesis of G4 histidine-maltose PPI dendrimers first with histidine (R1 ) and then with maltose (R2 ). Conjugation with histidine and maltose neutralizes the positive charge of the primary amino groups [22].*

dendron and terminal groups which could be used for dendrimer functionalization. The number of surface functional groups of the dendrimer depends on the degree of dendrimer branching (**Figure 1**). For example, PPI or PAMAM dendrimers of the second generation have 16 functional groups on their surface, the third generation has 32, and the fourth dendrimer generation has 64 functional groups. Strikingly, the number of terminal groups increases exponentially, while the size increases linearly. The terminal groups on the dendrimer surface can be used for surface modification and dendrimer functionalization. Such modifications could change dendrimers' surface charge and, for example, reduce toxicity associated with a cationic surface charge as reviewed by Appelhans et al. [23]. Dendrimers are most commonly synthesized using divergent or convergent different synthetic pathways [24]. Importantly, the high tunability of dendrimers' surface allows endless possibilities for dendrimers' biomedical applications, for example, for pharmaceutical applications, the terminal groups can be functionalized with different active conjugates such as specifically targeting antibodies, drugs, metal ions or imaging agents, and more [25]. Moreover, several research groups demonstrated that some types of dendrimers are able to cross the BBB [22, 26–28], showing their applicability for the research and possibly treatment of brain diseases.

In the present chapter, I summarize the experimental evidence showing that functionalized poly(propylene imine) dendrimers may provide multitargeting properties for dendrimers increasing their potential for the treatment of AD.
