**4. Conclusions**

As a mechanism, neuroprotection in CNS indications where protein misfolding occurs is detrimental, exacerbating the disease by creating inflammation in the local area that leads to the degeneration of nearby neurons. In the case of AD, neuroinflammation occurs when Aβ plaques are recognised by circulating microglial cells, initiating an immune response and releasing pro-inflammatory molecules that lead to the neurodegeneration that is found in patients with AD. The neuroprotective response of microglia in effect begins the deterioration of the brain, calling for therapeutic intervention to aid in neuroprotection.

Current therapeutics used as therapy for AD are all neuromodulatory, addressing the symptoms related to the disease instead of the underlying mechanism. About 73% of the current cohort of therapeutics in clinical trials for AD is DMTs, indicating the need for a therapeutic that either slows or stops the progression of the disease. DMTs targeting the amyloid cascade are of particular interest from a neuroprotective standpoint due to Aβ plaques initiating neuroinflammation. Targeting inflammation and Aβ plaques and fragments will only slow the progression of the disease requiring a more robust target that can stop disease progression. The role of BACE1 in Aβ generation provides an ideal target for therapeutics although it has proved elusive in the past, with trials into SMD inhibitors for BACE1 being halted due to safety concerns from off-target effects.

To develop an ideal therapeutic for BACE1, a molecule that lies somewhere between SMEs and biologics is required. Peptides offer attractive properties from both classes of therapeutic specifically a relative lack of toxicity and great specificity, both of which are ideal for combating CNS indications. Although peptides are seen as inadequate for use as therapeutics, many approved peptide therapies have shown the ability of peptides to be modified, improving qualities that were lacking initially. With further advancements in the field of peptide synthesis and modifications, the number of peptide therapeutics in clinical trials, not just for AD but other indications, will likely increase. Similarly, the number of approved therapies, offering a promising outlook for diseases where therapeutic needs are currently unmet, is likely to increase.
