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Alzheimer’s Disease (AD) is characterized by deposition of Amyloid-Beta Peptide (Aβ), which is produced from post-translational processing of Amyloid Precursor Protein (APP). The goal of this short review is to outline the major aspects of the biology of APP and the importance of APP in Alzheimer’s Disease. Subsequently, we briefly review current concepts regarding the potential targeting of APP processing in order to influence the ramifications of AD. Studies are underway to assess methods of altering the regulation of the APP gene as well as the regulation of the post-translational processing of APP. The complexity of APP processing has made the identification of new treatments for AD difficult. Future methods of targeting APP processing and expression are discussed. *Correspondence to: Andrew B. Bonner, Auburn University College of Veterinary Medicine, Scott-Ritchey Research Center Auburn, Alabama, USA, E-mail: abb0046@auburn.edu Received: August 20, 2019; Accepted: August 27, 2019; Published: August 30, 2019 The Biology of APP and Related Proteins that Contribute to Dementia Characteristics of the Most Common Type of Dementia: Alzheimer’s Disease Post-translational modifications of Amyloid Precursor Protein (APP) are related to the Dementia disorder; Alzheimer’s Disease (AD) [1-3]. The incidence and pathophysiology of Dementia and Alzheimer’s Disease is important to consider when assessing genetic implications. Dementia is a broad category of many disorders that involve memory and cognitive impairment [1-3]. As the U.S. population continues to age, this problem will continue to increase as most types of dementia occur in later stages of life. Due to the immense physical, emotional, and financial toll that dementia can have on patients and their families, the importance of the development of therapies for this disorder continues to grow. Alzheimer’s Disease (AD) is the most common type of dementia with approximately 30 million patients currently affected by this disease around the world. It is estimated that 75% of all patients with dementia have AD [1]. The two main types of AD include early onset disease, which is generally caused by inherited genetic factors and late onset disease, which is hypothesized to be caused by a combination of genetic and environmental factors [1,4]. Early onset AD is rare, accounting for around 5% of cases of AD. As its name suggests, this type of AD displays symptoms in individuals at an earlier age than late onset AD. Early onset AD generally occurs during the fourth or fifth decade of life. Late onset AD is the more common form of AD and less likely to have identifiable genetic origins. Symptoms of late onset AD usually begin during the sixth or seventh decades of life. Many of the factors that contribute to late onset AD have yet to be determined and will be the focus of many ongoing research efforts [4]. The two primary pathophysiological hallmarks of Alzheimer’s disease are Neurofibrillary Tangles (NFTs) and β-amyloid (Aβ) plaques. These hallmarks have been studied since the early description of the disease by Alois Alzheimer in 1906 [5]. Although this review focuses on the formation of Aβ from APP, a brief introduction of NFT’s and Tau is warranted. Neurofibrillary Tangles (NFTs) and Tau Protein in AD NFTs are formed from hyperphosphorylated tau proteins, and they are known to form in the intraneuronal space in patients with AD [6]. Although APP has the strongest genetic link to AD, the Tau protein is also involved, and the interaction of APP and Tau remains the subject of much investigation. The Tau protein is known to facilitate the function and production of microtubules from tubulin. The Tau protein is associated with the formation of NFTs under conditions in which there is dysfunction of the kinases or phosphatases that interact with the Tau protein. This dysfunctional state leads to hyperphosphorylated Tau protein and the subsequent accumulation of tangles in the intraneuronal space [5]. Studies have also shown that the extent of NFT accumulation is correlated with the degree and duration of symptoms experienced by patients with AD [6,7]. Although there is clearly an association between the formation of NFTs and AD, the nature of this association is not clear as it has been shown that NFTs are not specific for just AD. NFTs are also present in other neurodegenerative diseases such as Parkinson’s Disease and posttraumatic dementia [6,8]. The fact that NFT’s are non-specific for AD is important. This finding has led to studies that are seeking to delineate the integral components that are specific to AD. Therefore, in more recent years, much attention has shifted to APP processing as a probable basis for AD. However, the interaction of APP and Tau remains an important area of investigation. Characteristics of the APP Gene and APP The APP gene encodes for Amyloid Precursor Protein. The APP gene is located on chromosome 21q21.3 and is approximately 240 kilobases in length (some variation in forms of APP). The location of the gene has been verified through studies performed on individuals Bonner AB (2019) Amyloid Precursor Protein (APP) processing and potential targets for Alzheimer’s Disease Volume 4: 2-7 Biomed Genet Genomics, 2019 doi: 10.15761/BGG.1000146 with Down’s Syndrome. These studies show that the isoform of APP that is found in Aβ plaques is duplicated along with all other genes found on chromosome 21 in individuals with Down’s Syndrome. The early onset of AD in patients with Down’s Syndrome suggests a link of APP expression in AD pathology [4,9]. The genetic analyses of patients with AD have resulted in the discovery of many familial-associated mutations (FAM) of the APP gene that are believed to lead to the disease (10). These mutations occur in areas that encode for regions of the protein that will later result in increased Aβ production following post-translational processing of the APP protein [10]. Figure 1 outlines this process. It is noteworthy that genetic analyses of patients with AD have also revealed many mutations of the Presenilin genes (PS1 and PS2), which encode for the catalytic subunit of γ-secretase, an enzyme involved in the post-translational modification of APP [10-13]. The process of these post-translational modifications will be discussed in detail later. In mammals, the APP gene has two paralogs, APP like protein 1(APLP1) and APP like protein 2 (APLP2). The functions of these paralogs are mostly consistent in mammals [8,13]. The paralogs of the APP gene (APLP1 and APLP2) are unable to yield Aβ through post-translational processing. This characteristic is distinct to the APP gene [8,14]. APP is a transmembrane protein, which has been linked to neurogenesis and the regulation of neural differentiation. There is a high level of expression of APP during brain development although APP has also been shown to be expressed in most tissues. Studies have shown that overexpression of APP causes differentiation, across different cell lines, to neuronal states [8,15-17]. Despite this evidence, investigators are still investigating the primary function of APP. In order to determine the function of APP and its complex relation to AD, it will be important to better understand the above noted mechanisms that modify APP. Additionally, the breadth of interactions of APP with other cellular events will require much study in the future. Post-Translational Modifications of APP For many years, it has been known that there are two major branches in the post-translational processing of APP. These two branches have been termed the amyloidogenic pathway and the non-amyloidogenic pathway (Figure 1), although recently, the simplicity of this terminology has been called into question as the two pathways have other important interactions in the development of Aβ and AD (3,18-21). These two major branches of post-translational modification involve three secretases: β-secretase, γ-secretase, and α-secretase (Figure 1). Again, recent reports have suggested that the simplicity of this system may be more complex with the recent discovery of additional secretases (η, δ, and alternative β-secretases) that interact with APP, and lead to metabolites that are the subject of current investigations (16,19). Even though this model of amyloidogenic/non-amyloidogenic APP processing may be more complex than originally believed, it has served as an important foundation for the understanding of the biology of APP processing and the components of Aβ in AD. Figure 1. The two major pathways involved in post-translational processing of Amyloid Precursor Protein (APP) are depicted. Top: The non-amyloidogenic pathway utilizes the dual action of α-secretase and γ-secretase, which results in the truncated form of beta-amyloid (Aβ) known as P3. Bottom: The amyloidogenic pathway utilizes the dual action of β-secretase and γ-secretase to form Aβ Bonner AB (2019) Amyloid Precursor Protein (APP) processing and potential targets for Alzheimer’s Disease Volume 4: 3-7 Biomed Genet Genomics, 2019 doi: 10.15761/BGG.1000146 The first major pathway of post-translational APP processing, the amyloidogenic pathway, is depicted in Figure 1 [18,19]. This pathway begins as APP is cleaved by β-secretase to produce a soluble molecule, sAPPβ, that is secreted into the extracellular matrix and another molecule, βAPP-CTF, that remains bound to the membrane. The important difference between the two pathways, that are displayed in Figure 1, is the cut sites of β-secretase and α-secretase. The β-secretase cleaves APP at a location that does not interfere with the eventual formation of Aβ, while the α-secretase cleaves APP at a location that disrupts the formation of Aβ. The cut site of the β-secretase is essentially the first branch point in the difference between the amyloidogenic and non-amyloidogenic pathways of APP. βAPP-CTF is eventually cleaved by γ-secretase which results in the distribution of Aβ peptide i