Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases

Abstract

Developing effective treatments for neurodegenerative diseases is one of the greatest medical challenges of the 21st century. Although many of these clinical entities have been recognized for more than a hundred years, it is only during the past twenty years that the molecular events that precipitate disease have begun to be understood. Protein aggregation is a common feature of many neurodegenerative diseases, and it is assumed that the aggregation process plays a central role in pathogenesis. In this process, one molecule (monomer) of a soluble protein interacts with other monomers of the same protein to form dimers, oligomers, and polymers. Conformation changes in three-dimensional structure of the protein, especially the formation of beta-strands, often accompany the process. Eventually, as the size of the aggregates increases, they may precipitate as insoluble amyloid fibrils, in which the structure is stabilized by the beta-strands interacting within a beta-sheet. In this review, we discuss this theme as it relates to the two most common neurodegenerative conditions-Alzheimer's and Parkinson's diseases.

Figure 1

Pathological hallmarks of Alzheimer’s and Parkinson’s diseases. (A) Tangles and plaques in Alzheimer’s disease. Neurofibrillary tangles are intraneuronal and consist of paired helical filaments, the subunit of which is a microtubule-associated protein called tau that has been phosphorylated at multiple sites (dark staining structures). Amyloid plaques are extracellular and are largely composed of a ~4-kDa protein called the amyloid β-protein (Aβ) (round diffuse structures). See Acknowledgements for source information on panel A. (B) Lewy bodies in Parkinson’s disease. Nerve cell with 3 Lewy bodies that are double-stained for α-synuclein (brown) and ubiquitin (blue). Where only α-synuclein is stained, the color appears as pale reddish-brown, but where ubiquitin also is stained, the superposition of color gives a dark black and brown appearance. The blue staining is not seen on its own, because all the ubiquitin-immunoreactive structures are also positive for α-synuclein. The halo of each Lewy body is strongly immunoreactive for ubiquitin, whereas both the core and the halo of each Lewy body are immunoreactive for α-synuclein. Bar, 10 μm. Panel B has been reproduced from Figure 3 of Spillantini et al. (96), © 1993–2005 by the National Academy of Sciences of the USA, all rights reserved.

Figure 2

Production of Aβ by proteolytic cleavage from APP followed by association of Aβ to form oligomers and fibrils, showing potential targets for anti-amyloid therapies. Aβ, the gray shaded box, is cleaved from APP by sequential action of 2 proteases; β-secretase carries out the initial cleavage to form the N-terminus of Aβ; γ-secretase then cleaves the C99 stub to produce the C-terminus of Aβ. The parallel dotted lines represent a membrane bi-layer in which part of the C-terminal region of APP is anchored. Hence γ-secretase activity is a protease that cleaves a substrate within a membrane. Production of Aβ by secretase action leads to Aβ monomer, the concentration of which in the steady state is a balance between formation and degradation. Monomers can associate to form small oligomers that increase in size and eventually lead to fibril formation. One anti-amyloid strategy is to inhibit the enzymatic action of either secretase (shown by a black cross). A second strategy is to remove soluble and deposited Aβ using antibodies (shown as semicircles).

Figure 3

The Aβ hypothesis: an increase in the concentration of Aβ, especially the 42–amino acid form, is the underlying cause for the pathological features of Alzheimer’s disease.

Figure 4

Summary of α-synuclein’s role in Parkinson’s disease pathology. Cellular α-synuclein levels or chemical structure may be altered by overexpression, mutations, or chemical modifications (such as phosphorylation, nitration, oxidation, exposure to metal ions or toxins, or adduct formation with dopamine quinone). The increased oxidative environment of dopaminergic neurons is likely to exacerbate some of these processes, making these cells especially vulnerable. The end result is increased oligomer formation that may damage mitochondrial membranes. The amyloid-containing Lewy body is likely to be much less toxic than this precursor, and it may be the case that cells that rapidly produce Lewy bodies survive best. Other mutations in parkin, PINK1, and DJ-1 are likely to compromise the ability of mitochondria to resist stress.