Article

Pathogenic Protein Seeding in Alzheimer Disease and Other Neurodegenerative Disorders

Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Annals of Neurology (Impact Factor: 9.98). 10/2011; 70(4):532-40. DOI: 10.1002/ana.22615
Source: PubMed

ABSTRACT

The misfolding and aggregation of specific proteins is a seminal occurrence in a remarkable variety of neurodegenerative disorders. In Alzheimer disease (the most prevalent cerebral proteopathy), the two principal aggregating proteins are β-amyloid (Aβ) and tau. The abnormal assemblies formed by conformational variants of these proteins range in size from small oligomers to the characteristic lesions that are visible by optical microscopy, such as senile plaques and neurofibrillary tangles. Pathologic similarities with prion disease suggest that the formation and spread of these proteinaceous lesions might involve a common molecular mechanism-corruptive protein templating. Experimentally, cerebral β-amyloidosis can be exogenously induced by exposure to dilute brain extracts containing aggregated Aβ seeds. The amyloid-inducing agent probably is Aβ itself, in a conformation generated most effectively in the living brain. Once initiated, Aβ lesions proliferate within and among brain regions. The induction process is governed by the structural and biochemical nature of the Aβ seed, as well as the attributes of the host, reminiscent of pathogenically variant prion strains. The concept of prionlike induction and spreading of pathogenic proteins recently has been expanded to include aggregates of tau, α-synuclein, huntingtin, superoxide dismutase-1, and TDP-43, which characterize such human neurodegenerative disorders as frontotemporal lobar degeneration, Parkinson/Lewy body disease, Huntington disease, and amyotrophic lateral sclerosis. Our recent finding that the most effective Aβ seeds are small and soluble intensifies the search in bodily fluids for misfolded protein seeds that are upstream in the proteopathic cascade, and thus could serve as predictive diagnostics and the targets of early, mechanism-based interventions. Establishing the clinical implications of corruptive protein templating will require further mechanistic and epidemiologic investigations. However, the theory that many chronic neurodegenerative diseases can originate and progress via the seeded corruption of misfolded proteins has the potential to unify experimental and translational approaches to these increasingly prevalent disorders.

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    • "This may be particularly true if the connected areas are energetically challenged, such that these regions experience elevated excitation under oxidative stress or conditions of age-related impairment (Kapogiannis and Mattson, 2011). One hypothesis of the spread of AD pathology arose from the similarities to prion disease (Jucker and Walker, 2011). This is the view that AD pathology may be driven by progressive seeded aggregation of misfolded proteins, which spreads to interconnected neurons (Brettschneider et al., 2015 "
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    ABSTRACT: The pathogenesis of Alzheimer’s disease (AD) has been postulated to preferentially impact specific neural networks in the brain. The olfactory system is a well-defined network that has been implicated in early stages of the disease, marked by impairment in olfaction and the presence of pathological hallmarks of the disease, even before clinical presentation. Discovering the cellular mechanisms involved in the connectivity of pathology will provide insight into potential targets for treatment. We review evidence from animal studies on sensory alteration through denervation or enrichment, which supports the notion of using the olfactory system to investigate the implications of connectivity and activity in the spread of pathology in AD.
    Full-text · Article · Dec 2015 · Frontiers in Aging Neuroscience
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    • "Understanding the molecular and cellular mechanisms underlying this specific vulnerability of certain cell types and brain regions, as formulated by the principle of pathoclisis (Vogt and Vogt, 1951) provides a prerequisite for our understanding of brain pathology. Alzheimer's disease (AD) and Parkinson's disease (PD) are two disorders where much insight has been obtained recently about the hierarchical distribution of neuropathological hallmarks (Braak et al., 2003; Jucker and Walker, 2011). AD is histopathologically characterized by intracellular neurofibrillary tangles (NFT), composed of Tau aggregates and extracellular senile plaques, formed by fibrillary aggregates of the Ab-peptide (Bramblett et al., 1993; Selkoe, 2000, 2003; Chow et al., 2010). "
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    • "Our results can also be interpreted in the light of the recent notion that WM injury in AD has a central role on the way the disease strikes and progresses. A series of recent studies has provided evidence for a prion-like pathological transmission of A and tau aggregates in AD from neuron to neuron along WM connections [10] [11] [12]. Interestingly, in prion diseases, such as Creutzfeldt-Jakob disease, it has been recently demonstrated [44] that WM damage is not simply due to secondary degeneration, but is likely due to a direct effect of prion aggregation. "
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    ABSTRACT: Background: Longitudinal MRI studies in Alzheimer's disease (AD) are one of the most reliable way to track brain changes along the course of the disease. Objective: To investigate the evolution of grey matter (GM) atrophy and white matter (WM) damage in AD patients, and to assess the relationships of MRI changes with baseline clinical and cognitive variables and their evolution over time. Methods: Clinical, neuropsychological, and MRI assessments (T1-weighted and diffusion tensor [DT]-MRI) were obtained from 14 patients with AD at baseline and after a 16 ± 3 month period. Lumbar puncture was obtained at study entry. At baseline, AD patients were compared to 37 controls. GM atrophy progression was assessed with tensor-based morphometry and GM volumes of interest, and WM damage progression using tract-based spatial statistics and tractography. Results: At baseline, patients showed cortical atrophy in the medial temporal and parietal regions and a widespread pattern of WM damage involving the corpus callosum, cingulum, and temporo-occipital, parietal, and frontal WM tracts. During follow up, AD patients showed total GM atrophy, while total WM volume did not change. GM tissue loss was found in frontal, temporal, and parietal regions. In addition, AD patients showed a progression of WM microstructural damage to the corpus callosum, cingulum, fronto-parietal and temporo-occipital connections bilaterally. Patients with higher baseline cerebrospinal fluid total tau showed greater WM integrity loss at follow up. GM and WM changes over time did not correlate with each other nor with cognitive evolution. Conclusion: In AD, GM atrophy and WM tract damage are likely to progress, at least partially, independently. This study suggests that a multimodal imaging approach, which includes both T1-weighted and DT MR imaging, may provide additional markers to monitor disease progression.
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