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Pathology
Protein misfolding and aggregation is seen with many neurodegenerative diseases. Based on pathological findings, parkinsonian syndromes are classified into α-synucleinopathies (PD, DLB and MSA) and primary tauopathies (PSP and CBD). For pathological lesions used in postmortem diagnosis of parkinsonism, see figure 1.
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Figure 1.
In Parkinson's disease (PD), there is loss of pigmented neurons from the substantia nigra and remaining neurons may be very sparse (A). Lewy bodies can be observed in residual neurons (A, inset) and are highlighted, together with Lewy neuritis, using α-synuclein immunohistochemistry (B). Lewy bodies and Lewy neurites may be present in significant numbers in the neocortex (C, frontal cortex). In multiple system atrophy (MSA), α-synuclein is primarily deposited in the form of glial cytoplasmic inclusions in oligodendrocytes (D, putamen) and may also form inclusions in neuronal cytoplasm and nuclei (arrow) (E, pontine nuclei). In progressive supranuclear palsy tau forms, aggregates in neurons and glia, giving rise to tufted astrocytes (F, caudate) and neurofibrillary tangles (G, pontine nuclei). A characteristic feature of corticobasal degeneration (CBD) is the astrocytic plaque, formed from aggregated tau in the distal processes of astrocytes (H, parietal cortex). In CBD, tau also accumulates in neurons in the form of neurofibrillary tangles (H, inset a) and in oligodendrocytes as coiled bodies (H, inset b). (A) Haematoxylin and eosin; (B–D) α-synuclein immunohistochemistry; (F–H) tau immunohistochemistry. Bar in (A) represents 100 μm in (C); 50 μm in (A, D–G); 25 μm in inset A, B and H. Pathological images kindly provided by Dr Janice Holton, Queen Square Brain Bank for Neurological Disorders, London.
α-Synuclein (α-Syn) has been found to be the major constituent of the intracellular aggregates in Lewy bodies and Lewy neurites (pathological hallmark of PD and DLB) and in the glial cytoplasmic inclusions in MSA. The presence of abnormally aggregated tau proteins in the form of neurofibrillary tangles, for example, are diagnostic of PSP. Tau-positive intracellular inclusions are the neuropathological findings in CBD. Even though there are also neurofibrillary tangles in AD, Aβ plaques are closely tied to the primary disease process and thus AD is considered to be a secondary tauopathy. FTD can also have underlying tau pathology.
There is often some overlap between syncleinopathies and tauopathies (for a review, see ref. 7). Co-occurrence of tau and α-Syn pathology has been found in neurons and oligodendrocytes in AD, PD and DLB. α-Syn has complex and dynamic interactions with tau. Each of these two proteins has the tendency to seed the aggregation of the other. α-Syn induces aggregation and polymerisation of tau, which promotes formation of intracellular amyloid-tau inclusions. Similar interactions have been described between α-Syn and Aβ pathology.
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