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Neurodegenerative Disorders: Alzheimer’s Disease

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Neurodegenerative Disorders: Alzheimer’s Disease

1. Amyloid Precursor Protein (APP) Alzheimer’s disease (AD) remains a major cause of senile dementia, which is characterised by an impairment of neuronal and synaptic function in addition to the accumulation of β-amyloid plaque and formation of neurofibrillary tangles within distinct portions of the brain (De Strooper and Annaert, 2000). Progression of this distinct pathology of neurodegeneration does not typically vary from patient to patient, beginning in cerebral cortex before targeting the hippocampus, neocortex as well as the sub-cortical nuclei (Braak and Braak, 1995). The role of amyloid precursor protein (APP) in the pathogenesis of Alzheimer’s disease is pivotal. The cleavage of APP by the proteases β and γ- secretase releases β-amyloid (Aβ) peptides which results in aggregation of the peptides due to misfolding to form fibrils of Aβ which comprise the key components of amyloid plaque deposits in the brains of AD patients (Glenner and Wong, 1984). Amyloid precursor protein (APP) is a trans-membrane glycoprotein which normally functions in synapse formation as well as axonal elongation. The protein possesses a small cytoplasmic domain but is composed primarily of a large extracellular domain. Processing of APP in the extracellular domain by α or β- secretase results in the complete removal of the protein’s ectodomain which gives rise to an accumulation of sizeable and soluble derivatives of APP referred to as APPsα of APPsβ in addition to membrane- linked carboxyl-terminal fragments (CTFα and CTFβ). The key β- secretase in neurons is β-site APP cleaving enzyme (BACE1). BACE1 is capable of cleavage at the α-secretase site within the Aβ domain of the APP protein to allow liberation complete Aβ peptides following further processing by γ- secretase (Vassar et al., 1999). The γ- secretase machinery is comprised of a number of proteins such as PEN2, APH1, presenilin and nicastrin which form a complex that confers the proteolyic activity of the enzyme. Extracellular cleavage of APP at the carboxyl terminus of Aβ is mediated by γ- secretase, giving rise to the formation of one of two products: either p3, which is a 3kDa product generated in collaboration with α-secretase activity, or Aβ, which is generated in cooperation with BACE1 activity, in addition to the APP intracellular domain (AICD) (Iwatsubo, 2004).
Figure 1: The α-secretase pathway leads to the formation of P3 and is non- amyloidogenic, whereas the β-secretase pathway is amyloidogenic, resulting in the formation of the amyloid plaque-forming Aβ protein. Products of both pathways are critical for the maintenance of neuron development and function and usually only about 10% of APP enters the amyloidogenic pathway depending on age, and other environmental causes (Figure adapted from La Ferla et al., 2007)
Figure 1: The α-secretase pathway leads to the formation of P3 and is non- amyloidogenic, whereas the β-secretase pathway is amyloidogenic, resulting in the formation of the amyloid plaque-forming Aβ protein. Products of both pathways are critical for the maintenance of neuron development and function and usually only about 10% of APP enters the amyloidogenic pathway depending on age, and other environmental causes (Figure adapted from La Ferla et al., 2007)
APP Processing
APP Processing

Other proteins besides Aβ have been implicated in the pathogenesis of AD, most notably Tau and to a lesser extent, Apiloprotein E (ApoE). Tau is a microtubule-associated protein that when hyper-phosphorylated comprises the main component of neurofibrillary tangles, another hallmark of AD. When Tau is hyper-phosphorylated, conformational changes within the protein prevent normal binding to microtubules. Tau instead detaches and forms helical filaments making them more prone to aggregation, and it is this accumulation of Tau protein along with microtubule rearrangements that trigger neurodegeneration (Götz et al., 2004). ApoE is normally found circulating in the cardiovascular system where it interacts with low density lipoprotein receptors (LDLRs) to regulate plasma lipoprotein as well as cholesterol levels. This protein is manufactured in the liver before being transported to numerous organs of the body. In the brain however, ApoE is generated by astrocytes and is thought to contribute to neuronal growth and plasticity in addition to the formation of synapses and dendrites. Three alleles of the apoE gene exist, giving rise to three distinct isoforms, ApoE2, E3 and E4. Each isoform is associated with a distinct risk of disease, and the presence of the ApoE4 isoform has been linked to an increased propensity to develop AD (Warrington and Rodriguez, 2010).

2. Models of Alzheimer’s Disease

Due to the remarkable genomic similarities between mouse and man, transgenic mice have traditionally been utilised as models of human disease in an attempt to uncover novel therapies. This method of overexpressing or introducing a mutation to a gene of interest is advantageous when investigating disorders were a single gene has been implicated in pathogenesis if the disease. However, AD is a multifactorial disorder and since causes of the disease remain undetermined, it is difficult to genetically engineer a mouse model that will fully replicate the complete pathology and phenotype of AD demonstrated in humans. Many mouse models may exhibit one or several of the pathological characteristics AD such as neurofibrillary tangles and amyloid plaque deposition within the brain, but without the expected phenotype of memory impairment and confusion, and vice versa. For example, the mouse model PD-APP is equipped with mutations in the gene encoding APP which effectively replicates the memory deficits and amyloid plaque deposits observed in human AD. However, even though Tau is found to be hyper phosphorylated in this model, neurofibrillary tangles are notably absent. An obvious disadvantage of utilising single transgenic mouse models is that because AD is an age related disorder, the expected phenotype and pathology is not evident until mice reach adulthood. Mouse models possessing mutations in more than one gene such as the APP/PS1 mouse can be utilised in order to enhance disease progression in younger individuals, thus accelerating research efforts. Unfortunately, the same problems with effectively replicating disease pathogenesis is encountered with this mouse model also, with neurofibrillary tangles being absent from affected individuals (Ebrahimi and Schluesener, 2013).

The Samaritan Alzheimer’s rat model (FAB rat) is considered a far superior model of AD compared with the mouse models. As opposed to the aforementioned mouse models which have been genetically altered to replicate AD progression of varying success rates, the FAB rat has been modified surgically which enables the all hallmarks of AD pathogenesis (i.e. amyloid plaques, NFTs, neuronal degeneration and cognitive impairment) to be reproduced effectively and simultaneously. It was found that injecting a cocktail containing Aβ42, BSO and Fe2+ into Long Evans rat brains which are already predisposed to developing neurodegenerative disorders, was sufficient to induce an AD-like disease over time. There are clear advantages of the FAB rat model over traditional transgenic mice models such as a reduced disease induction period of 4 weeks compared with ~12 months. Transgenic mouse models are only useful for the study of familial forms of AD, whereas the FAB rat is a model of sporadic AD which is most common (Lecanu at al., 2006).

3. ER Stress and Parkinson’s Disease

Parkinson’s disease (PD) is the most commonly occurring neurodegenerative disorder after AD, with pathological hallmarks that include the incidence of intra neural cytoplasmic inclusion bodies commonly referred to as Lewy bodies, in addition to selected dopaminergic neuron death within the substantia nigra pars compacta of the brain. In 90% of affected individuals PD develops in its sporadic form, but the molecular mechanisms contributing to the pathogenesis of the disease have yet to be fully elucidated. It has been postulated that selected neuronal degeneration maybe triggered by a variety of causes including environmental factors such as the use of pesticides and other similar chemicals, oxidative stress, hindered mitochondrial activity as well as damage to the ubiquitin-proteasome system (UPS) (Healy et al., 2004). More recently, endoplasmic reticulum (ER) stress in response to misfolded proteins has been directly implicated in PD progression. A cell enters a state of ER stress in response to the build-up of incorrectly folded proteins in the ER lumen. The unfolded protein response (UPR) is triggered in an attempt to counteract these potentially toxic conditions within the cell. The UPR comprises an intracellular signalling pathway which ultimately targets incorrectly folded proteins for degradation. However, during extended or harsher periods of ER stress, apoptosis-promoting signals may be stimulated which culminates in death of the cell as a last resort (Wang and Takahashi, 2007).

ER Stress and Transmissible Spongiform Encephalopathy

Transmissible Spongiform Encephalopathies (TSEs), or prion diseases as they are more commonly known, comprise a group of transmissible disorders such as bovine spongiform encephalopathy (BSE), Creutzfeldt-Jacob disease (CJD), as well as scrapie. TSE pathology is characterised by a build-up of a misfolded form of the prion protein (PrP5c), which is also resistant to protease in the brain. The accumulation of the mutant PrP5c triggers widespread apoptosis of neurons, and by extension, dissolution of brain tissue. Interestingly, Wild type PrP and the pathological PrP5c share identical sequences of amino acids, differing only in the degree of β-sheets present in their secondary structure (Prusiner, 1998). Studies conducted by Rane et al. have provided evidence to suggest a direct link between the pathogenesis of TSEs and ER stress. Accumulation of PrP in the secretory pathway during periods of ER stress is cleverly avoided by directing PrP out of the ER and into the cytosol where it is then target for degradation. However, in times of acute cellular stress, accumulation of substantial quantities PrP protein in the cytosol may prove toxic to cell, promoting degeneration of neurons as evident in TSEs (Rane et al., 2008).

4. Bitan’s “Molecular Tweezers”

To date, research efforts for the discovery of novel therapies for the treatment of AD have for the most part been focused on the temporary alleviation of symptoms rather than cure. Bitan’s “molecular tweezers” is considered a more promising approach for the treatment of AD in comparison to conventional methods as it was demonstrated for the first time in a mammalian model, a compound that is capable of successfully traversing the blood brain barrier in mice and reversing the process of synaptotoxicity, thereby removing deposits of amyloid-β plaque as well as accumulation of tau. The tweezer itself is composed of “C” shaped molecule called CLR01 capable of targeting other proteins at lysine residues through electrostatic and hydrophobic interactions. Bitan’s study has shown that mice with AD are capable of recovering their memory and learning capabilities when treated with CLR01 without any toxic side effects. Crucially, the “molecular tweezers” method does not interfere with normal cellular processes, targeting only the aberrantly folded proteins within a cell, as opposed to more the conventional therapies which involve the targeting of selected proteins by inhibitors (Attar and Bitan, 2013) This suggests that “molecular tweezer” based therapies provide a much safer alternative than the more established techniques, meaning a patient can begin treatment at the early stages of disease.

Bibliography

Attar A and Bitan G: Curr Pharm Des. Jul 11. Disrupting Self-Assembly and Toxicity of Amyloidogenic Protein Oligomers by "Molecular Tweezers"- from the Test Tube to Animal Models (2013).

Braak H and Braak E: Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging; 16(3): 271–284 (1995).

De Strooper B and Annaert W: Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci, 113:1857-1870 (2000).

Ebrahimi A and Schluesener H: Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease. Ageing Research Reviews vol. 12 issue 1 January, 2013. p. 116-140 (2013).

Glenner G and Wong C: Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885-890 (1984).

Götz J, Schild A, Hoerndli F and Pennanen L: Amyloid-induced neurofibrillary tangle formation in Alzheimer's disease: insight from transgenic mouse and tissue-culture models. Int J Dev Neurosci, 22:453-465 (2004).

Healy DG, Abou-Sleiman PM and Wood NW PINK, PANK, or PARK? A clinicians' guide to familial Parkinsonism. Lancet Neurol. 3: 652–662 (2004).
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La Ferla, FM., Green, KN, and Oddo, S: Intracellular amyloid-β in Alzheimer's disease. Nature Reviews Neuroscience 8, 499-509 (2007)

Lecanu L, Greeson J and Papadopoulos V: Beta-amyloid and oxidative stress jointly induce neuronal death, amyloid deposits, gliosis, and memory impairment in the rat brain. Pharmacology 76: 19-33 (2006).

Prusiner SB: Prions. Proc. Natl. Acad. Sci. USA 95: 13363–13383 (1998).

Rane N, Kang S, Chakrabarti O, Feigenbaum L and Hegde R: Reduced Translocation of Nascent Prion Protein During ER Stress Contributes to Neurodegeneration Dev Cell. September; 15(3): 359–370 (2008).

Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G and Citron M: Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science, 286:735-741 (1999).

Wang HQ and Takahashi R: Expanding insights on the involvement of endoplasmic reticulum stress in Parkinson's disease. Antioxid Redox Signal. May; 9(5):553-61 (2007).

Warrington A and Rodriguez M: Method of identifying natural antibodies for remyelination. J Clin Immunol. May; 30 Suppl 1:S50-5 (2010).

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