Spreading of pathology in neurodegenerative diseases: a focus on human studies

Abstract

The progression of many neurodegenerative diseases is thought to be driven by the template-directed misfolding, seeded aggregation and cell-cell transmission of characteristic disease-related proteins, leading to the sequential dissemination of pathological protein aggregates. Recent evidence strongly suggests that the anatomical connections made by neurons - in addition to the intrinsic characteristics of neurons, such as morphology and gene expression profile - determine whether they are vulnerable to degeneration in these disorders. Notably, this common pathogenic principle opens up opportunities for pursuing novel targets for therapeutic interventions for these neurodegenerative disorders. We review recent evidence that supports the notion of neuron-neuron protein propagation, with a focus on neuropathological and positron emission tomography imaging studies in humans.

Figure 1. Hypothetical molecular mechanisms of prion-like disease protein transmission in neurodegenerative diseases

In template-directed misfolding, the deposited pathological disease proteins are transformed from their normal conformation, via intermediates, into fibrillar species. These species have the properties of amyloid (for instance, a fibrillar ultrastructure that consists of sheets of β-strands) and serve as templates to drive normal physiological versions of the protein to adopt similar structural alterations. In a self-perpetuating process, the progressive seeded aggregation of conformationally changed proteins results in intracellular aggregates that fragment into ‘daughter seeds’. Finally, in cell–cell transmission, pathological proteins spread to anatomically interconnected neurons and adjacent glial cells via an autocatalytic chain-reaction-like process.

Figure 2. Sequential topographical dissemination of non-prion proteins in neurodegenerative diseases

In all panels, the pathology is first detected in areas delineated by darker colours and subsequently in regions shown in lighter colours. a, b | In Alzheimer disease, tau aggregates develop in the locus coeruleus (LC), then in the transentorhinal and entorhinal regions and subsequently in the hippocampal formation and in broad areas of the neocortex (NC). c, d | In contrast to tau pathology, amyloid-β deposits in Alzheimer disease are first observed in the NC and are then detected in allocortical, diencephalic and basal ganglia structures (in a caudal direction) and in the brainstem, and occasionally in the cerebellum (CB). e, f | The progression of α-synuclein-immunoreactive Lewy body and Lewy body and neurite pathology in Parkinson disease follows an ascending pattern from the brainstem to the telencephalon. The earliest lesions can be detected in the olfactory bulb (OB), as well as in the dorsal motor nucleus of the vagus nerve (DMX) in the medulla oblongata. At later stages, the α-synuclein aggregate pathology is found more rostrally through the brainstem via the pons and midbrain, in the basal forebrain and, ultimately, in the NC. g, h | In amyotrophic lateral sclerosis cases with a low burden of TAR DNA-binding protein 43 (TDP43) pathology, TDP43 inclusions are seen in the agranular motor cortex (AGN), in the brainstem motor nuclei of cranial nerves XII–X, VII and V, and in α-motor neurons in the spinal cord. Later stages of disease are characterized by the presence of TDP43 pathology in the prefrontal neocortex (PFN), brainstem reticular formation, precerebellar nuclei, pontine grey and the red nucleus. Subsequently, prefrontal and postcentral neocortices, as well as striatal neurons, are affected by pathological TDP43, before the pathology is found in anteromedial portions of the temporal lobe, including the hippocampus. AC, allocortex; BFB, basal forebrain; BN, brainstem nuclei; BSM, brainstem somatomotor nuclei; ENT, entorhinal cortex; MTC, mesiotemporal cortex; SC9, spinal cord grey-matter lamina IX; SN, substantia nigra; TH, thalamus. Part f reprinted from Neurobiology of Aging, 24, Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease, 197–211, © 2003, with permission from Elsevier.