*2.1.2.1 Inflammation*

As the step preceding neurodegeneration, inflammation is a clear target for therapeutic intervention. Neuroinflammation has been a target in therapeutic development after the increasing recognition that glial activation is an important step in the process of neurodegeneration. Therapeutics targeting neuroinflammation have been evaluated in previous cohorts of clinical trials, all producing similar results of ineffectiveness at slowing cognitive decline [31]. The principle of anti-inflammatory targeting aims to prevent the off-target damage to neighbouring neurons, delaying the onset of neurodegeneration. However, without removing the stimulus causing neuroinflammation, therapeutics are fighting a losing battle. Factors such as rate of cognitive decline, severity of the neuroinflammatory response, and disease state play a role in anti-inflammatory and immunomodulatory drug discovery proving difficult as the timing of the intervention is critical [32]. Anti-inflammatory therapeutics made up 16% of therapeutics in clinical trials in 2019, many repurposed for AD [19]. As a sole therapeutic intervention for AD, anti-inflammatories are not ideal. Combined therapy using anti-inflammatories and a disease-clearing therapeutic will likely show a high rate of success in alleviating chronic inflammation caused by AD.

### *2.1.2.2 Amyloid-β*

Aβ is an attractive target for neuroprotection, with many possible angles to approach the underlying cause of the disease. Two methods aimed at targeting Aβ plaques have been employed in clinical trials: immunotherapy, targeting the plaques for removal by the immune system using a vaccine or monoclonal antibodies (mAbs), and anti-aggregation, preventing the Aβ fragments from forming the plaques. In 2019, nine immunotherapies were part of clinical trials: three active immunotherapies (vaccines), CAD106, ABvac40 and GV1001, and six passive immunotherapies (mAbs), aducanumab, crenezumab, gantenerumab, solanezumab, LY3002813 and LY3372993 [19].

Thoroughly tested in animal models, Aβ vaccines exhibit the ability to prevent the formation of new Aβ plaques and contribute to the clearance of pre-deposited plaques [33]. Immunising an individual to Aβ grants the long-term effects of antibody production. However, immunisation can be difficult where adverse reactions in older individuals may occur due to inconsistent or lack of an immune system, as well as selecting a specific epitope that will not target similar structures [34]. Clinical trials into AN1792, an adjuvant vaccine of the full-length Aβ peptide and QS-21, were stopped due to development of meningoencephalitis in some patients [35]. Second-generation anti-Aβ vaccines such as CAD106 have proven to be efficacious in phase 2 clinical studies, eliciting Aβ-specific antibodies and showing long-term safety promising to be a valuable therapeutic option [36].

Passive immunotherapies have a major advantage over Aβ immunisation in that there is a consistent antibody titre [34]. Initial intravenous administration

**25**

*An Alternate View of Neuroprotection with Peptides in Alzheimer's Disease*

of immunoglobulin preparations containing high levels of human anti-Aβ42, which showed a significant improvement in cognition and lower levels of Aβ [33]. However, similar to the other discontinued anti-Aβ mAb therapies, largescale testing proved efficacy to be low or non-existent. A risk found in trials with Bapineuzumab was the presence of abnormalities after imaging the brain, identifying the onset of vasogenic oedema in 3 of the 10 participants. These abnormalities were coined as ARIA-E, amyloid-relating imaging abnormalities-vasogenic effusions, and are seen as a risk in large-scale studies of mAb therapies [37]. Many mAbs in 2019 are still plagued with these obstacles, presenting safety concerns surrounding ARIA-E, although some mAbs in Phase 2/3 or 3 trials are looking closer

As a target class, combined therapy of immunotherapeutics and anti-aggregates stand the highest chance of clearing deposited and newly generated Aβ fragments. Aggregation of Aβ monomers only make it more difficult to clear from the extracellular space with neuroprotective mechanisms naturally clearing monomers that build-up over time. From this perspective, Aβ is targeted as both monomers and plaques. Solanezumab targets Aβ monomers before they can aggregate. Targeting the causal feature of amyloid-based microglial activation, anti-aggregates prevent the conversion of Aβ monomers into oligomers or fibrils [38]. Many natural and synthetic compounds have been identified as potential anti-aggregates for Aβ; however, the only anti-aggregate for amyloidogenesis in clinical trials in 2019 is a combination therapy of polyphenol extract from grapeseeds and resveratrol [19]. The current cohort of anti-aggregates is not indicative of knowledge of the field, with other compounds such as epigallocatechin-3-gallate and curcumin showing

promising results for both anti-aggregation and other purposes [39].

Modulating the upstream step of plaque formation provides an encouraging target as prevention of deposition of Aβ fragments may stop the neuroinflammatory response before it starts. A "one size fits all" therapy for secretase modulation is not possible as all three secretase enzymes play different roles in the generation of Aβ fragments, each requiring a different form of modulation specific to

Inhibitors of BACE1 and gamma secretase have thus far showed limited Aβ clearance in clinical trials, even after demonstration of excellent inhibition in preclinical animal models [40]. Studies into gamma secretase found that it was the last step in Aβ fragment generation and an ideal target to prevent the build-up of fragments and formation of plaques [41]. Semagacestat was identified as potential drug candidate for clinical trials in decreasing Aβ levels, only after Phase III in the IDENTITY trials was it found to have adverse effects on Notch signalling [42]. Identified as a drug with a higher selectivity for APP over Notch in preclinical studies, Avagacestat was another gamma secretase inhibitor that showed similar effects to Semagacestat forcing the discontinuation of the trials due to adverse dose-limiting effects [43]. The adverse effects and lack of efficacy had quashed further research into gamma secretase inhibitors; however, a new look into gamma secretase as a target has identified that it is available for modulation, specifically altering the cleavage site of the enzyme. NGP 555 is a promising SME gamma secretase modulator that has showed promising results *in vivo,* significantly lower-

ing levels of Aβ42 through a shift of cleavage site in gamma secretase [44].

*DOI: http://dx.doi.org/10.5772/intechopen.91065*

than ever at slowing the progression of AD.

*2.1.2.3 Secretase inhibitors*

*2.1.2.3.1 Gamma secretase*

their role in the processing of APP.

#### *An Alternate View of Neuroprotection with Peptides in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.91065*

of immunoglobulin preparations containing high levels of human anti-Aβ42, which showed a significant improvement in cognition and lower levels of Aβ [33]. However, similar to the other discontinued anti-Aβ mAb therapies, largescale testing proved efficacy to be low or non-existent. A risk found in trials with Bapineuzumab was the presence of abnormalities after imaging the brain, identifying the onset of vasogenic oedema in 3 of the 10 participants. These abnormalities were coined as ARIA-E, amyloid-relating imaging abnormalities-vasogenic effusions, and are seen as a risk in large-scale studies of mAb therapies [37]. Many mAbs in 2019 are still plagued with these obstacles, presenting safety concerns surrounding ARIA-E, although some mAbs in Phase 2/3 or 3 trials are looking closer than ever at slowing the progression of AD.

As a target class, combined therapy of immunotherapeutics and anti-aggregates stand the highest chance of clearing deposited and newly generated Aβ fragments. Aggregation of Aβ monomers only make it more difficult to clear from the extracellular space with neuroprotective mechanisms naturally clearing monomers that build-up over time. From this perspective, Aβ is targeted as both monomers and plaques. Solanezumab targets Aβ monomers before they can aggregate. Targeting the causal feature of amyloid-based microglial activation, anti-aggregates prevent the conversion of Aβ monomers into oligomers or fibrils [38]. Many natural and synthetic compounds have been identified as potential anti-aggregates for Aβ; however, the only anti-aggregate for amyloidogenesis in clinical trials in 2019 is a combination therapy of polyphenol extract from grapeseeds and resveratrol [19]. The current cohort of anti-aggregates is not indicative of knowledge of the field, with other compounds such as epigallocatechin-3-gallate and curcumin showing promising results for both anti-aggregation and other purposes [39].
