ANÁLISIS PROBLEMÁTICA ACUEDUCTOS

Aβ is thought to play a central role in AD pathogenesis. Hence targeting Aβ production, aggregation and removal may be of therapeutic benefit. To inhibit Aβ production, drugs that target APP processing by inhibition of secretase activities are

being developed. Studies have also reported that up-regulation of α-secretase in APP processing decreases Aβ yield and improves cognitive behaviour in transgenic mice, implying that this may be a viable treatment for AD (Caccamo et al 2006, Lin et al 1999). In addition, APP undergoes γ-secretase cleavage to release Aβ, thus selectively

inhibiting γ-secretase activity is also considered to be a viable therapeutic strategy.

The applied dose of γ-secretase inhibitor would have to be carefully controlled to

avoid blocking important signaling pathways, such as those downstream of Notch (Bergmans & De Strooper 2010). BACE1 (β-secretase), the other enzyme that is involved in Aβ generation has multiple substrates in vivo (Hu et al 2006, Kim et al

2007a) but fewer than γ-secretase. Thus, modification of BACE1 activities without

interfering with important physiological signaling may be a more promising potential therapeutic strategy for AD.

Inhibition of Aβ aggregation has been proposed to be a prospective viable AD treatment, and indeed cognitive benefits have been reported both in animals and in humans who were given inhibitors of Aβ aggregation (Adlard et al 2008, Lannfelt et

al 2008, Olcese et al 2009). However, one must be careful when considering AD by

inhibition of Aβ aggregation because the exact Aβ aggregation species causing Aβ mediated neurotoxicity remains unknown. Blocking aggregation of Aβ could end up being more detrimental if small aggregates are more neurotoxic, or if aggregation inhibiting aggregation increases the formation of longer aggregates.

Inadequate removal of Aβ from the brain may contribute to amyloid accumulation in the CNS, thus therapeutic strategies aimed at increasing Aβ removal and clearance are being in investigated. They may be a more promising approach given that both β- and

γ-secretase inhibition may have off-target effects. For example, APP transgenic mouse studies indicate that increased astrocytic lysosome biogenesis may promote uptake, trafficking and degradation of Aβ, which suggests that activation of astrocytic lysosomes may facilitate Aβ removal and attenuate amyloid induced AD pathogenesis (Xiao et al 2014). In addition, modulation of neprilysin expression, the most potent Aβ -degrading enzyme (Shirotani et al 2001) may provide an alternative opportunity for intervention (Nalivaeva et al 2012). Neprilysin may act on a wide range of peptide substrates with biological functions. Nevertheless, this problem may be overcome by modifying the neprilysin active site in such a way as to make it more specific to for

Aβ degradation (Webster et al 2014). A variety of proteins such as apolipoprotein E

and J have been described that interact with Aβ and regulate its ability to across the BBB (Calero et al 2012). Aβ may be degraded in the circulatory system after transport into the blood by either Aβ-degrading enzymes or by immune response cells, such as monocytes that have been shown to clear vascular Aβ (Michaud et al 2013).

1.6.2.1.1 Aβ immunotherapy

Aβ immunotherapy is a potential AD treatment that has been advanced recently because of its ability to decrease brain Aβ accumulation (Frenkel et al 2000). Aβ immunotherapy can be achieved by active immunization, which is performed by injecting AD subjects with synthetic intact synthetic Aβ or synthetic Aβ fragments bound to a carrier protein to mediate an immune response that generate antibodies against Aβ (Bard et al 2000). The antibody bound Aβ may be removed via Fc receptor -mediated clearance by microglia (Bard et al 2000). Aβ immunization results in reduced CNS Aβ load and less neuritic dystrophy, as well as improved cognition

compared to non-treated controls (Bard et al 2000, Masliah et al 2005, Schenk et al 1999, Serrano-Pozo et al 2010). However, active immunotherapy of AD patients was terminated in phase II clinical trials due to an incidence of meningoencephalitis which may have been caused by T cell-induced inflammatory responses (Liu et al 2009, Orgogozo et al 2003).

Passive immunization is another Aβ immunotherapy that is currently being tested in clinical trails. In passive immunization, the antibodies directly against Aβ are administrated to the patients. Using this approach, the antibody may interact with plaques thereby inducing a scavenging response in microglia (Bohrmann et al 2012). Nevertheless, clinical trails using anti-Aβ monoclonal antibodies (bapineuzumab and ponezumab) were discontinued due to the lack of cognitive improvement and to adverse side effects (vasogenic cerebral oedema) (Blennow et al 2012, Burstein et al 2013, Landen et al 2013, Salloway et al 2014). However, a humanized antibody, crenzumab, with the decreased Fc receptor affinity, was safely given at a high dose to patients with a good safety outcome in a phase I trials that has seen the drug moved to phase II trials (Adolfsson et al 2012). Another humanized monoclonal antibody, solanezumab, that recognizes the middle region of Aß and binds soluble monomeric forms of Aß, shows positive effects in mild AD (Lannfelt et al 2014). Nevertheless, phase III trials of solanezumab was failed in mild to moderate AD (Doody et al 2014). This may be because this treatment was administrated too late in the course of AD (Laske 2014).

Taken together, these results indicate that immunotherapy for AD treatment is perhaps one of the most promising areas for future investigation. However, a major challenge for both active and passive immunization may be the delivery of synthetic

Aβ antibodies across the BBB into the CNS (Spencer & Masliah 2014). Besides, Aβ immunotherapy, especially actives immunization in particular has been found to produce persistent autoimmune side effects in an AD mice model. This was manifested by microglial infiltration, which not only activated microglia to engulf Aβ but also importantly led to disruption and degeneration of local tissues (Liu et al 2009). Moreover, it has not been easy to identify any clinical benefits in Aβ immunotherapy in phase II – III clinical trials (Blennow et al 2014). Therefore, active Aβ immunotherapy for AD treatment needs to be more intensively investigated. However, ethics considerations may prohibit further clinical trails. Currently passive immunization strategies demonstrate the feasibility of Aβ clearance, however, more studies will be needed to determine dosage and the stage at which antibodies should be delivered.