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


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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    ABSTRACT: Alzheimer's disease and Parkinson's disease are neurodegenerative disorders characterized by the misfolding of proteins into soluble prefibrillar aggregates. These aggregate complexes disrupt mitochondrial function, initiating a pathophysiological cascade leading to synaptic and neuronal degeneration. In order to explore the interaction of amyloid aggregates with mitochondrial membranes, we made use of two in vitro model systems, namely: (i) lipid vesicles with defined membrane compositions that mimic those of mitochondrial membranes, (ii) respiring mitochondria isolated from neuronal SH-SY5Y cells. External application of soluble prefibrillar forms, but not monomers, of amyloid-beta (Aβ42 peptide), wild-type α-synuclein (α-syn), mutant α-syn (A30P and A53T) and tau-441 proteins induced a robust permeabilisation of mitochondrial-like vesicles, and triggered Cytochrome c release (CCR) from isolated mitochondrial organelles. Importantly, the effect on mitochondria was shown to be dependent upon cardiolipin, an anionic phospholipid unique to mitochondria and a well-known key player in mitochondrial apoptosis. Pharmacological modulators of mitochondrial ion channels failed to inhibit CCR. Thus, we propose a generic mechanism of thrilling mitochondria in which soluble amyloid aggregates have the intrinsic capacity to permeabilise mitochondrial membranes, without the need of any other protein. Finally, six small-molecule compounds and black tea extract were tested for their ability to inhibit permeation of mitochondrial membranes by Aβ42, α-syn and tau aggregate complexes. We found that black tea extract and rosmarinic acid were the most potent mito-protectants, and may thus represent important drug leads to alleviate mitochondrial dysfunction in neurodegenerative diseases.
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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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    ABSTRACT: Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (Abeta) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics. Within the past decade convincing data has arisen positioning the soluble prefibrillar Abeta-aggregates as the prime toxic agents in AD. However, different Abeta aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Abeta is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function. Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Abeta-aggregates than to focus on a single aggregate species for immunization.
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