Targeting Oligomers in Neurodegenerative Disorders: Lessons from α-Synuclein, Tau, and Amyloid-β Peptide

Abstract

Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Prion disease, Huntington's disease, and amyotrophic lateral sclerosis are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation in selected brain regions. The aggregates usually consist of insoluble fibrillar aggregates containing misfolded protein with β-sheet conformation. The most probable explanation is that inclusions and the aggregates symbolize an end stage of a molecular cascade of several events, and that earlier event in the cascade may be more directly tied up to pathogenesis than the inclusions themselves. Small intermediates termed as 'soluble oligomers' in the aggregation process might influence synaptic dysfunction, whereas large, insoluble deposits might function as reservoir of the bioactive oligomers. Compelling evidence suggests the role of misfolded proteins in the form of oligomers might lead to synaptic dysfunction, neuronal apoptosis and brain damage. However, the mechanism by which oligomers trigger neurodegeneration still remains mysterious. The aim of this article is to review the literature around the molecular mechanism and role of oligomers in neurodegeneration and leading approaches toward rational therapeutics.

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

“…[21][22][23] Because immunotherapeutic strategies displayed great promise in animal models of AD, a strong effort was made by the industry to inhibit generation of toxic Ab aggregates and remove soluble and aggregated Ab deposited in the brains of AD patients by both active and passive anti-Ab immunotherapy strategies. [24][25][26][27][28][29][30][31] Data from active vaccine trials indicate that, to be effective, anti-Ab therapeutic should induce high titers of anti-Ab antibodies without activation of autoreactive T cells.…”

Anle138b and related compounds are aggregation specific fluorescence markers and reveal high affinity binding to α-synuclein aggregates

“…The amyloid aggregates are considered to play an important role in the pathogenesis of neurodegenerative diseases [3][4][5][6][7]. Furthermore, recent experiments pointed out that not only the fibrillar structures but especially the formation of smaller, highly cytotoxic oligomeric forms [8] might lead to neuronal loss [9][10][11][12]. At present, the mechanism by which protein aggregation to fibrillar and oligomeric structures leads to dysfunction of neurons and neuronal loss is not really known.…”

Protein Interaction Module–assisted Function X (PIMAX) Approach to Producing Challenging Proteins Including Hyperphosphorylated Tau and Active CDK5/p25 Kinase Complex

“…For the examination of their overall phosphorylation status, denatured tau and p-tau were purified via a boiling method that exploited the heat resistance of tau and p-tau (2). In this approach, the conditions for induction and cell lysate preparation were identical to those described above.…”

“…Certain diseases and cancers have been linked to the deregulation of many PTMs. For example, abnormal hyperphosphorylation of tau and ␣-synuclein is intimately associated with the onset and progression of Alzheimer disease and Parkinson disease, respectively (2). Germline mutations of the highly related histone acetyltransferases CBP and p300 cause the Rubinstein-Taybi syndromes that predispose patients to tumors, lymphoma, and other diseases (3,4).…”