Neurodegenerative Disease

  • The role of β-Amyloid Peptides in Alzheimer's Disease

    Alzheimer's disease (AD) is a neurodegenerative disease and the most common cause of dementia. AD is characterised by progressive cognitive decline and memory dysfunction.   The two major histopathological lesions in AD are senile plaques composed of diverse beta-amyloid (Aβ) peptide aggregates and neurofibrillary tangles composed of tau proteins aggregates.  The dysregulation of Aβ production, folding, clearance and degradation result in the accumulation of Aβ and formation of senile plaques.  However, the correlation between Aβ plaques density and the severity of AD is ambiguous. Studies show that elevated levels of Aβ, oligomeric Aβ and protofibrils can induce calcium dyshomeostasis, trigger activation of caspase 3, or regulate a variety of signalling cascades (such as NMDARs and AMPARs) which lead to synapse dysfunction, shrinkage, collapse and neuronal cell death. It has been suggested that soluble nonfibrillar intermediates are the initiators of AD, whereas mature fibril formation represent the later stages of AD pathology.

    Amyloid precursor protein (APP) is sequentially cleaved by β- and γ-secretase to form Aβ peptides. β-secretase cleaves APP to release soluble APPβ and exposes a membrane bound C-terminal fragment (CTF99). Intramembrane proteolysis of CTF99 by γ-secretase initially occurs at various ε-cleavage sites, followed by carboxypeptidase cleavage at γ-cleavage sites to produce 39-43 amino acid Aβ peptide fragments. Aβ (1-40) is the most abundant form followed by Aβ (1-42). Aβ peptides undergo a conformation switch from α-helical to β-sheet structure. The Aβ β-sheets can adopt parallel or anti-parallel arrangements within protofilaments depending on the peptide properties. The β-sheet content is linked to Aβ insolubility. The longer forms of Aβ are more hydrophobic and fibrillogenic. Aβ (1-42) has been identified as the major component in senile plaques. An increase in Aβ (1-42) to Aβ (1-40) ratio has been shown to increase the propensity for Aβ aggregation. The fibrillar state has also been shown to be associated with protease resistance. The solubility and composition of Aβ species in different populations of amyloid deposits correlates to the disease state of the patient.

    Synthetic Aβ peptides are widely used to examine the structure, assembly and the activity of Aβ monomers, soluble oligomers and insoluble fibrils. Aβ peptides provide a means to assess the dynamics of nucleation and elongation of homogeneous and heterogeneous Aβ fibrils under various physiological conditions. Studies using Aβ peptides and their truncated variants provide an insight into biophysical properties and fibrillogenic regions and help identify intermediate species that contribute to Aβ toxicity. Furthermore, Aβ peptides are subject to post-translational modifications, such as oxidation, phosphorylation, isomerisation, nitration and glycosylation, which exhibit different physiological and pathological properties. Understanding the effects of various modifications will help establish factors that influence Aβ amyloidogenicity.

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  • Focus on Myelin Oligodendrocyte Glycoprotein (MOG)

    Myelin oligodendrocyte glycoprotein (MOG) is a type I integral membrane protein on the extracellular surface of oligodendrocytes in the outermost lamellae of the myelin sheath. MOG can exist as monomeric and dimeric species. Its extracellular localisation facilitates its functions as a homophilic adhesion receptor, where it plays a role in the completion, compaction and maintenance of the myelin.

    Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disorder of the central nervous system (CNS) characterized by myelin destruction and axonal degeneration. MOG has been identified as a key autoantigen for demyelination in MS and experimental autoimmune encephalomyelitis (EAE), an animal model that resembles MS. Although MOG is a minor component of the CNS, it is highly immunogenic and can stimulate the activation of T-cell and B-cell responses.

    Immunization of rodents with native or recombinant MOG or synthetic MOG derived peptides induces an inflammatory response and initiates an immune response against myelin, causing damage and degeneration of the CNS. A number of MOG peptide fragments have shown to be encephalitogenic determinants, including MOG (1-22), MOG (35-55), MOG (92-106). Crystal structure studies of the MOG extracellular domain in a homodimer complex reveal that residues within the MOG 1-22, 35-55 and 92-106 map onto the face of the β-sheet and participate in the dimerization interface. This suggests a link between the dimeric form of MOG and a failure of immunological tolerance to MOG seen in MS.

    Studies using various MOG derived peptides show that the MOG (35-55) fragment is the most potent encephalitogen and the immunodominant epitope for T cell response.  MOG (35-55) induced EAE models can be used to recapitulate all three MS subtypes, which are relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and secondary progressive MS (SPMS). Depending on the MOG (35-55) dose, immunized mice are presented with varying degrees of neuropathogical impairment, immune infiltration, ascending paralysis, demyelinating lesions, axon loss and gliosis in the spinal cord and brain. MOG (35-55) induced EAE models can provide an insight into elucidating the immunopathological mechanism of MS progression and facilitate in the development of novel therapeutics.


    MOG (35-55) acid Mouse, Rat



    MOG (35-55) amide Mouse, Rat



    MOG (92-106) Mouse, Rat


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