Role of Protein Aggregates in Neurodegenerative Diseases
Protein aggregation is an established pathogenic mechanism in AD, although little is known about the initiation of this process in vivo. As human brain research largely depends on the results of postmortem studies, an insight into the early stages of the disease, when protein aggregates are most likely to occur, is difficult. Novel and better animal models would therefore be very helpful to study the progress of AD in humans. The clinical course of the disease in humans could be monitored by brain imaging (CT, MRI). The exact connection between protein aggregates, such as extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), the latter composed of hyperphosphorylated microtubule associated protein (TAU), in the brains of patients with AD, and neurodegeneration is therefore still unknown. It does seem that the AD is caused by the accumulation of amyloid plaques and neurofibrillary fibers, although this is not absolutely confirmed and generally accepted (Medeiros et al., 2011). Stronger evidence that aggregates do trigger neurodegeneration (the so-called amyloid hypothesis) and are not just a consequence of the neurodegeneration, is provided by mutations in the gene for the amyloid beta precursor protein (APP) present in some human patients with AD (Selkoe, 1991; Hardy and Higgins, 1992; Hardy and Selkoe, 2002; Lansbury and Lashuel, 2006). Similarly, amyloid plaques are present in different brain regions in dogs with CCD clinical symptoms, and they can be present even before clinical signs of this disease become obvious.
In general, age-related neurodegenerative disorders are complex and multifaceted pathologies, wherein the formation of large aggregates and/or high concentrations of toxic proteins prevent the proper function of neuronal cells, leading to ischemia and eventually tissue removal. The spread of AD pathology follows a characteristic topographic pattern, different for the two proteins involved in the pathology, Aβ and TAU (Brettschneider et al., 2015). TAU aggregates first develop in the locus coeruleus, then in entorhinal cortex followed by hippocampus and neocortex. Aβ plaques firstly appear in the neocortex, and later in allocortical, diencephalic and basal ganglia structures and in the brainstem (Brettschneider et al., 2015; Jucker and Walker, 2018). These aggregates spread in a prion-like manner, forming intracellular and extracellular deposits. TAU, Aβ, and also Parkinson disease associated α-synuclein, exist in different conformational variants (‘strains’) that show seeding properties and exert different levels of neurotoxicity, which could be the source of heterogeneity of neurodegenerative diseases (Aguzzi, 2014). The seeding potential of these aggregates was recently substantiated by demonstrating propagation of structural variants of Aβ in their distinct conformations through template-directed folding of naïve Aβ peptides (Condello and Stöehr, 2018). Prion-like transmission and seeding has been also observed for TAU (DeVos et al., 2018). Similar mechanism may be involved in young, pre-depositing APP transgenic mice which developed cerebral β-amyloidosis and associated pathology after being intracerebrally injected with Aβ-containing brain extracts from human patients with AD (Meyer-Luehmann et al., 2006; Langer et al., 2011). Interestingly, even intraperitoneal inoculation with Aβ extracts induced β-amyloidosis in the brains of APP transgenic mice after prolonged incubation times (Eisele et al., 2010). Likewise, soluble oligomers from blood and cerebrospinal fluid (CSF) of an aged dog with CCD were neurotoxic to human neuroblastoma cell line, and canine CSF derived Aβ induced the in vitro aggregation of synthetic human Aβ peptides (Rusbridge et al., 2018). Spreading of misfolded Aβ oligomers in a prion-like mechanism might also exploit exosomes, which can seed Aβ not only as vehicles for the neuron-to-neuron transfer (Zheng et al., 2017; Sardar Sinha et al., 2018) but also between distant brain regions (i.e., from the dentate gyrus to other regions of hippocampus and to the cortex) (Zheng et al., 2017).