*2.1.2.3 Secretase inhibitors*

*Neuroprotection - New Approaches and Prospects*

what seems to be simple obstacles.

*2.1.2 Targets of the amyloid cascade*

ing chronic inflammation caused by AD.

ezumab, LY3002813 and LY3372993 [19].

*2.1.2.1 Inflammation*

*2.1.2.2 Amyloid-β*

modification to the structure of the therapeutic may be required to reach the target from the blood stream or the tissue at the site of injection. Although there are common issues regarding ideal therapeutic properties of biologics, new technology is improving every day allowing therapeutic development of biologics to overcome

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 alleviat-

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, solan-

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

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

**24**

option [36].

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 their role in the processing of APP.
