**Abstract**

Neuroprotection plays a crucial role in everyday life, maintaining a clean environment in the central nervous system to allow for normal functioning. In Alzheimer's disease and other neurodegenerative disorders, neuroprotection may have two roles. Under standard circumstances, the immune system protects the CNS, but sometimes it can exacerbate the pathophysiology of some diseases through neuroinflammation leading to further degeneration. Alzheimer's disease is fast getting out of control, with no new approvals in therapeutics since 2003, and of those approved, all target symptomatic treatment. Initiated by a microglial response to Aβ plaques, therapeutic development should focus on the amyloid cascade as a neuroprotective measure for Alzheimer's disease. This chapter will examine the status of the types of therapeutics in clinical trials for Alzheimer's disease, offering insights into peptides as an area of opportunity for neuroprotection and detailing considerations for the use of peptides in Alzheimer's disease.

**Keywords:** Alzheimer's disease, peptides, neuroinflammation, therapeutic development, CNS indications

#### **1. Introduction**

The central nervous system (CNS) consists of the brain and spinal cord, playing the role of control centre in the body. It is responsible for sending and integrating signals from around the body and coordinating activity. Protecting the CNS is crucial to sustaining life. Without this system, normal day-to-day functions such as breathing and eating would be compromised. Arguably, the most important organ in the CNS is the brain. This is protected from external physical injury by the skull and meninges, which provide a buffer against forceful trauma to the head. How does the brain protect itself from internal injury, such as a microbiological threat or other small molecules that invade the sterile environment? Bacteria, viruses and misfolded proteins are as much of a threat as physical impacts. However, there is no durable exterior to protect from these internal attacks. The next line of defence is the immune system, a complex network of specialised cells that aim to protect the body against these biological threats.

The immune response is key to maintaining the delicate environment of the CNS. However, the neuroprotective properties of the immune system may also be detrimental to the surrounding neurons. Immune cells release chemical mediators such as cytokines and histamine to damage foreign cells, but these mediators also damage sensitive structures that make up the brain. This process occurs in disorders where degeneration of cellular tissue in the brain is present. Disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) all exhibit progressive degeneration of specific neuronal cell populations [1, 2]. All four diseases are commonly found to exhibit misfolding, aggregation and accumulation of specific proteins. This hallmark feature is now widely accepted as a possible cause for these diseases and other neurodegenerative disorders [3–5]. Deposition of amyloid-forming proteins functions as the initiating step for neuroinflammation [6] activating pattern recognition receptors (PRRs) on microglia, the resident macrophages in the brain [6, 7]. To protect the brain, microglia recognise fragments of these misfolded proteins and secrete cytokines and chemokines. The release of these pro-inflammatory immunomodulators mediates neuroinflammation, attracting other immune cells such as astrocytes and perivascular macrophages to aid in innate immunity [8]. In most cases, activated microglia will clear the build-up of the pathogenic proteins resolving the immune response and subsequent inflammation.

In a typical immune response where resolution is achieved, clearance of the localised inflammation allows the surrounding tissue to return to normal conditions. When the immune response is not resolved, inflammation persists in the local area, potentially becoming toxic to neighbouring cells. Prolonged inflammation in a sensitive environment such as the CNS is highly likely to cause damage to neurons and other nearby cells, leading to local degeneration of tissue. Damage-associated molecular patterns (DAMPs) released from neurons in the inflamed area are recognised by PRRs on primed microglia. This further stimulates the release of pro-inflammatory molecules [9]. This persistent selfpropagating cycle of inflammation and necrosis causes the chronic inflammation that exacerbates the pathology of the disease. The notion that neuroprotection does more damage than it prevents has been explored recently, with some proposing that inflammation is the causative agent of neurodegeneration [10, 11]. To prevent neurodegeneration found in diseases like AD, neuroprotective therapeutics must be developed in order to prevent further inflammation and damage from occurring.

#### **1.1 Alzheimer's disease as a neuroinflammatory disorder**

Alois Alzheimer first discovered clusters of abnormal protein built up in the cerebral cortex of a patient in 1906. Alzheimer described these clusters as "thick bundles [that] appear at the surface of the cell", noting specifically that neurons in the upper layers of tissue had "disappeared" [12]. These bundles were later identified as the two major hallmarks of AD, hyperphosphorylated tau and aggregated amyloid-beta (Aβ). Alzheimer also noted glial cells clustered around the plaques, concurrent with the theory of an immune response to the extracellular deposits of Aβ plaques and cellular death. In 2019, we are still no closer to mapping out the nature of this disease than Alois was in 1906, with the pathophysiology of the disease still debated: which came first, the tau or the plaques? There have been several hypotheses considered over the nature of the disease; however, the two major hallmarks remain the most probable causes.

To describe the basis of the two major hypotheses is easy; the amyloid cascade involves the cleavage of a transmembrane protein known as amyloid-precursor protein (APP) by the aspartic-acid protease beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which leads to the extracellular aggregation of a peptide called Aβ, whereas the neurofibrillary tangle (NFT) theory posits that AD

**19**

space.

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

is caused by the hyperphosphorylation of tau, a soluble microtubule-associated

**2. Therapeutics for Alzheimer's disease: past, present and future**

In a 20-year period from 1998 to 2017, a total of 146 drugs in clinical trials were halted or had not received approval by the FDA [17]. In that same time, four cognitive-enhancing therapeutics had been approved, giving some hope that there is a chance to identify a therapeutic for AD. Therapeutics in the AD clinical trial pipeline are split into two major classes of mechanism of action (MOA): symptomatic treatments and disease-modifying therapies (DMTs). Symptomatic treatments aim to alleviate symptoms that are present with the onset of the disease easing the burden on the affected individuals. There are currently five therapies that have been approved for use in patients that exhibit symptoms derived from neurotransmitter disturbance in mild to severe cases of AD. Suppressing symptoms such as memory loss and cognitive decline do not address the underlying nature of the disease [18]. Symptomatic treatments are beneficial for family and friends, demonstrating modest and consistent benefits for cognition. However, the underlying cause of the disease remains unchanged in these therapies where the disease progresses into a more severe state. DMTs are treatments that alter the pathology of the disease, changing the long-term course of the disease. A large proportion of DMTs targets the major hallmarks of AD, NFTs and Aβ formation. Other DMTs are present that target alternative aspects of the disease; however, these alternative targets are mostly downstream effects of NFTs or Aβ plaques. Of major interest are DMTs that target the amyloid cascade, their primary goal is to reduce plaque load, clear plaque depositions, or reduce inflammation. The nature of this MOA is of a neuroprotective stance, theoretically with the ability to reduce the amount of neurodegeneration that occurs due to chronic inflammation from Aβ seeding in the extracellular

As of February 2019, 132 therapeutics were in clinical trials for AD, 96 of those classed as DMTs presenting an increase of 25 DMTs from 2018 [19, 20]. Therapeutics labelled as neuroprotective, anti-inflammatory and anti-amyloid in the 2019 cohort of clinical trials will be described as neuroprotective DMTs as they all target the amyloid cascade as the priming step of neuroinflammation. Neuroprotective DMTs are described as either prophylactic treatments or diseaseclearing treatments. Prophylactic treatment of AD aims at preventing the onset

Before establishing the effects of a therapeutic for neuroprotection in AD, the causative agent of neuronal death needs to be identified. Examining both hypotheses in detail reveals that the deposition of Aβ plaques has more of an effect on NFT formation than hyperphosphorylation of tau has on amyloid build-up [13, 14]. Arguments for both options are common place in discussion about AD; however, there are some key facts on why Aβ plaques are crucial in the development of neurodegeneration, and therefore the symptoms of AD. In transgenic mouse models, it has been shown that NFT formation succeeds Aβ deposition extracellularly [15, 16]. As a causal agent, tau is seen in other diseases such as frontotemporal lobar degeneration, progressive supranuclear palsy and Pick's disease. All of which form tau aggregates without an onset of Aβ deposition. The distinct immune response from Aβ plaque deposition indicates that the amyloid cascade is the driving factor of neurodegeneration in AD [10]. From a neuroprotective standpoint, preventing the amyloid cascade from generating and depositing Aβ plaques seems the most probable option for prevention of neurodegeneration from chronic

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

neuroinflammation.

protein that can aggregate intracellularly into NFTs.

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

*Neuroprotection - New Approaches and Prospects*

ing the immune response and subsequent inflammation.

**1.1 Alzheimer's disease as a neuroinflammatory disorder**

hallmarks remain the most probable causes.

such as cytokines and histamine to damage foreign cells, but these mediators also damage sensitive structures that make up the brain. This process occurs in disorders where degeneration of cellular tissue in the brain is present. Disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS) all exhibit progressive degeneration of specific neuronal cell populations [1, 2]. All four diseases are commonly found to exhibit misfolding, aggregation and accumulation of specific proteins. This hallmark feature is now widely accepted as a possible cause for these diseases and other neurodegenerative disorders [3–5]. Deposition of amyloid-forming proteins functions as the initiating step for neuroinflammation [6] activating pattern recognition receptors (PRRs) on microglia, the resident macrophages in the brain [6, 7]. To protect the brain, microglia recognise fragments of these misfolded proteins and secrete cytokines and chemokines. The release of these pro-inflammatory immunomodulators mediates neuroinflammation, attracting other immune cells such as astrocytes and perivascular macrophages to aid in innate immunity [8]. In most cases, activated microglia will clear the build-up of the pathogenic proteins resolv-

In a typical immune response where resolution is achieved, clearance of the localised inflammation allows the surrounding tissue to return to normal conditions. When the immune response is not resolved, inflammation persists in the local area, potentially becoming toxic to neighbouring cells. Prolonged inflammation in a sensitive environment such as the CNS is highly likely to cause damage to neurons and other nearby cells, leading to local degeneration of tissue. Damage-associated molecular patterns (DAMPs) released from neurons in the inflamed area are recognised by PRRs on primed microglia. This further stimulates the release of pro-inflammatory molecules [9]. This persistent selfpropagating cycle of inflammation and necrosis causes the chronic inflammation that exacerbates the pathology of the disease. The notion that neuroprotection does more damage than it prevents has been explored recently, with some proposing that inflammation is the causative agent of neurodegeneration [10, 11]. To prevent neurodegeneration found in diseases like AD, neuroprotective therapeutics must be developed in order to prevent further inflammation and damage

Alois Alzheimer first discovered clusters of abnormal protein built up in the cerebral cortex of a patient in 1906. Alzheimer described these clusters as "thick bundles [that] appear at the surface of the cell", noting specifically that neurons in the upper layers of tissue had "disappeared" [12]. These bundles were later identified as the two major hallmarks of AD, hyperphosphorylated tau and aggregated amyloid-beta (Aβ). Alzheimer also noted glial cells clustered around the plaques, concurrent with the theory of an immune response to the extracellular deposits of Aβ plaques and cellular death. In 2019, we are still no closer to mapping out the nature of this disease than Alois was in 1906, with the pathophysiology of the disease still debated: which came first, the tau or the plaques? There have been several hypotheses considered over the nature of the disease; however, the two major

To describe the basis of the two major hypotheses is easy; the amyloid cascade involves the cleavage of a transmembrane protein known as amyloid-precursor protein (APP) by the aspartic-acid protease beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), which leads to the extracellular aggregation of a peptide called Aβ, whereas the neurofibrillary tangle (NFT) theory posits that AD

**18**

from occurring.

is caused by the hyperphosphorylation of tau, a soluble microtubule-associated protein that can aggregate intracellularly into NFTs.

Before establishing the effects of a therapeutic for neuroprotection in AD, the causative agent of neuronal death needs to be identified. Examining both hypotheses in detail reveals that the deposition of Aβ plaques has more of an effect on NFT formation than hyperphosphorylation of tau has on amyloid build-up [13, 14]. Arguments for both options are common place in discussion about AD; however, there are some key facts on why Aβ plaques are crucial in the development of neurodegeneration, and therefore the symptoms of AD. In transgenic mouse models, it has been shown that NFT formation succeeds Aβ deposition extracellularly [15, 16]. As a causal agent, tau is seen in other diseases such as frontotemporal lobar degeneration, progressive supranuclear palsy and Pick's disease. All of which form tau aggregates without an onset of Aβ deposition. The distinct immune response from Aβ plaque deposition indicates that the amyloid cascade is the driving factor of neurodegeneration in AD [10]. From a neuroprotective standpoint, preventing the amyloid cascade from generating and depositing Aβ plaques seems the most probable option for prevention of neurodegeneration from chronic neuroinflammation.
