Article

Structure – Function Relationships of Pre-Fibrillar Protein Assemblies in Alzheimers Disease and Related Disorders

Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-7334, USA.
Current Alzheimer Research (Impact Factor: 3.89). 07/2008; 5(3):319-41. DOI: 10.2174/156720508784533358
Source: PubMed

ABSTRACT

Several neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and prion diseases, are characterized pathognomonically by the presence of intra- and/or extracellular lesions containing proteinaceous aggregates, and by extensive neuronal loss in selective brain regions. Related non-neuropathic systemic diseases, e.g., light-chain and senile systemic amyloidoses, and other organ-specific diseases, such as dialysis-related amyloidosis and type-2 diabetes mellitus, also are characterized by deposition of aberrantly folded, insoluble proteins. It is debated whether the hallmark pathologic lesions are causative. Substantial evidence suggests that these aggregates are the end state of aberrant protein folding whereas the actual culprits likely are transient, pre-fibrillar assemblies preceding the aggregates. In the context of neurodegenerative amyloidoses, the proteinaceous aggregates may eventuate as potentially neuroprotective sinks for the neurotoxic, oligomeric protein assemblies. The pre-fibrillar, oligomeric assemblies are believed to initiate the pathogenic mechanisms that lead to synaptic dysfunction, neuronal loss, and disease-specific regional brain atrophy. The amyloid beta-protein (Abeta), which is believed to cause Alzheimer's disease (AD), is considered an archetypal amyloidogenic protein. Intense studies have led to nominal, functional, and structural descriptions of oligomeric Abeta assemblies. However, the dynamic and metastable nature of Abeta oligomers renders their study difficult. Different results generated using different methodologies under different experimental settings further complicate this complex area of research and identification of the exact pathogenic assemblies in vivo seems daunting. Here we review structural, functional, and biological experiments used to produce and study pre-fibrillar Abeta assemblies, and highlight similar studies of proteins involved in related diseases. We discuss challenges that contemporary researchers are facing and future research prospects in this demanding yet highly important field.

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    • "Multiple lines of evidence demonstrate that the difference in peptide length is one of the key components for controlling early oligomerization. In fact, paranuclei and several other types of oligomer form exclusively from Aβ42 and not from Aβ40 [21]. Many other regions of the Aβ sequence have been discretely studied for their unique characteristics, for example , the central hydrophobic cluster, Aβ17–21 [22] [23], and M35 [24] [25] [26]. "
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    ABSTRACT: Amyloid β-protein (Aβ) is believed to cause Alzheimer's disease (AD); this belief is based largely on studies showing autosomal dominant inheritance of familial AD (FAD) due to mutations that increase brain concentration levels of Aβ or of particular forms of Aβ. However, how specifically this leads to AD is not clear. Several mutations have been identified inside the Aβ-coding region of the amyloid β protein precursor (APP); these mutations change both the biophysical characteristics of Aβ and the disease phenotype, such as age of onset of dementia and location and morphology of amyloid deposits. Characterizing the effects of the amino acid changes in Aβ on the protein's assembly and toxicity may help to identify Aβ regions particularly useful as drug targets. We summarize here key findings related to substitutions at positions 2, 6, 7, 16, 21-23, and 34 in Aβ and their relation to FAD.
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    • "The aberrant assembly of such diverse proteins into mature amyloid fibrils proceeds through the formation of intermediate oligomeric assemblies. These soluble prefibrillar species, which are typically transient and structurally heterogeneous, are now widely recognised as the primary toxic determinants in both AD and PD [8] [9] [10] [11] [12] [13] [14]. A landmark study using transgenic mice has shown that α-syn variants that specifically form oligomers were significantly more neurotoxic than α-syn variants that form fibrils. "
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    • "Thus, despite the reported presence of prefibrillar Aβ [27] the debate about the most relevant Aβ-species is still controversial. The identification of endogenous Aβ-aggregates is hampered owing to the dynamic and non-linear nature of aggregation and methodological limitations [28-30]. To this date the larger aggregates (e.g. "
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