Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Abstract

Experimental data indicate that transneuronal propagation of abnormal protein aggregates in neurodegenerative proteinopathies, such as sporadic Alzheimer's disease (AD) and Parkinson's disease (PD), is capable of a self-propagating process that leads to a progression of neurodegeneration and accumulation of prion-like particles. The mechanisms by which misfolded tau and a-synuclein possibly spread from one involved nerve cell to the next in the neuronal chain to induce abnormal aggregation are still unknown. Based on findings from studies of human autopsy cases, we review potential pathways and mechanisms related to axonal and transneuronal dissemination of tau (sporadic AD) and a-synuclein (sporadic PD) aggregates between anatomically interconnected regions. S poradic Alzheimer's disease (AD) and Parkinson's disease (PD) are human neurodegenerative disorders that do not occur in other vertebrate species. Pathological hallmark lesions in AD and PD involve only a few types of nerve cells, mainly projection neurons. These lesions develop at predetermined predilection sites and progress according to predictable patterns (Braak and Del Tredici 2009, 2015). In AD, disease-related lesions remain confined to the central nervous system (CNS), whereas in PD they develop not only in the CNS but also in the enteric (ENS) and peripheral (PNS) nervous systems. Both diseases are caused by misfolding of specific proteins that are associated with aberrant aggregation. AD is primarily characterized by pathological forms of the intraneuronal protein tau (Goedert et al. 2006;Iqbal et al. 2009) and, thereafter gradually, by extracellular deposits of the b-amyloid protein (Ab) (Alafuzoff et al. 2009;Haass et al. 2012;Masters and Selkoe 2012). In mature nerve cells, the highest concentrations of the protein tau usually are found in the axon. Key lesions in sporadic PD consist of aggregated forms of a-synuclein, a protein located chiefly in axons and their presynaptic terminals (Eisenberg and Jucker 2012;Jucker and Walker 2013;Kaufman and Diamond 2013;Goedert et al. 2014). Notably, all brain regions and all types of nerve cells consecutively involved in AD or PD are anatomically interconnected over considerable distances, thereby indicating that physical contact among such interconnected nerve cells plays a key role in the pathogenesis of both illnesses (Pearson et al. 1985;Saper et al. 1987;Pearson and Powell 1989;Pearson 1996;Duyckaerts et al. 1997;Braak and Del Tredici 2011b). Ab is deposited extracellularly and thus is not known to transfer from one nerve cell to the next in the neuronal chain (Fiala 2007;Kaufman and Diamond 2013).Here, we focus on potential pathways and mechanisms related to the postulated transmission and transneuronal dissemination of tau and a-synuclein between involved neurons and as yet uninvolved neurons in anatomically connected regions (Brundin et al. 2008Clavaguera et al. 2009Clavaguera et al. , 2013aDesplats et al. 2009;Luk et al. 2009;Angot et al. 2010 Angot et al. , 2012Frost and Diamond 2010;Goedert...

Insular cortex sub-region-dependent distribution pattern of α-synuclein immunoreactivity in Parkinson’s disease and dementia with Lewy bodies

“…In line with this, the granular insula connects to isocortical somatosensory and cingulate cortex and is affected in later stages of the disease [38]. Thus the cytoarchitecture and the connectivity of the insular subregions could provide a framework for the understanding of dissemination of α-synuclein pathology throughout the brain [11,21]. Considering the anterior insula connectivity, α-synuclein pathology and cell death in the agranular insula may also contribute to autonomic, cognitive and psychiatric symptoms in PD(D) and DLB [52].…”

Sleep and Human Aging

“…Beyond the medial temporal lobe, AD post-mortem studies have established that neurofibrillary tangles within the preoptic area of the hypothalamus correlate with the severity of prior fragmented sleep (Lim et al, 2014). Interestingly, tau deposition is also present in other sleep-regulating areas such as the locus coeruleus and basal forebrain and can be observed even in cognitively normal older adults (Braak and Del Tredici, 2016; Braak et al, 2011; Stern and Naidoo, 2015). This leads to the currently untested hypothesis that tau within these regions may trigger sleep abnormalities years before degenerative disease onset and, if such sleep disruption is specific, could serve as an early diagnostic biomarker (Holth et al, 2016).…”

Aberrant brain network connectivity in presymptomatic and manifest Huntington's disease: A systematic review

“…In HD, neurons in different brain regions accumulate abnormal deposits of misfolded protein, a histopathological hallmark shared with other proteinopathies, such as AD and PD (Braak & Del Tredici, 2016;Saudou & Humbert, 2016). Recent findings suggested that pathogenic proteins, such as beta-amyloid/Tau in AD and alphasynuclein in PD, can spread in a prion-like fashion via selective functionally connected neural networks, triggering specific clinical phenotypes of brain disorders (Brettschneider, Del Tredici, Lee, & Trojanowski, 2015;Jucker & Walker, 2011;Raj, Kuceyeski, & Weiner, 2012).…”