An autopsy report of three kindred in a Gerstmann-Sträussler-Scheinker disease P105L family with a special reference to prion protein, tau, and beta-amyloid

Abstract

Introduction: Gerstmann-Sträussler-Scheinker disease P105L (GSS105) is a rare variant of GSS caused by a point mutation of the prion protein (PrP) gene at codon 105 (proline to leucine substitution). It is clinically characterized by spastic paraparesis and dementia and histopathologically defined by PrP-plaques in the brain. This report describes a clinicopathological analysis of three autopsied kindred from a Japanese GSS105 family, plus a topological analysis of PrP, hyperphosphorylated tau (p-tau), and beta-amyloid (Aβ).

Methods: Using paraffin-embedded sections, we applied histology and single- and multiple-labeling immunohistochemistry for PrP, p-tau, and Aβ to the three cases. Comparative semi-quantitative analyses of tissue injuries and PrP-plaques were also employed.

Results: Case 1 (45 years old (yo)) and Case 2 (56 yo) are sisters, and Case 3 (49 yo) is the son of Case 2. Case 1 and Case 2 presented with spastic paraparesis followed by dementia, whereas Case 3 presented, not with spastic paraparesis, but with psychiatric symptoms. In Case 1 and Case 2, the brain showed tissue injuries with many PrP-plaques in the cerebral cortices, and the pyramidal tract showed myelin loss/pallor. In Case 3, the brain was least degenerated with a number of PrP-plaques; however, the pyramidal tract remained intact. In addition, p-tau was deposited in all cases, where p-tau was present in or around PrP-plaques. By double-labeling immunohistochemistry, the colocalization of p-tau with PrP-plaques was confirmed. Moreover in Case 2, Aβ was deposited in the cerebral cortices. Interestingly, not only p-tau but also Aβ was colocalized with PrP-plaques. In all cases, both three repeat tau and four repeat tau were associated with PrP-plaques.

Conclusions: The clinicopathological diversity of GSS105, which is possible even in the same family, was ascertained. Not only p-tau but also Aβ could be induced by PrP ("secondary degeneration"), facilitating the kaleidoscopic symptoms of GSS.

Keywords: Gerstmann-Sträussler-Scheinker disease P105L; autopsy; beta-amyloid; prion protein; spastic paraparesis; tau.

Figure 1

The family tree of the three cases is shown. Other than the three cases analyzed in this study (arrows), there is another sibling (*), a 55‐year‐old woman at death, who showed spastic paraparesis, dementia, and cerebellar dysfunction. Square, male; circle, female; diamond, an individual whose information of sex is unavailable; +, dead. Closed symbols indicate an individual with definite or possible GSS105‐associated symptoms

Figure 2

The comparative macroscopic and microscopic findings among the three cases. Left column (Case 1, a–j), middle column (Case 2, a–k), right column (Case 3, I–X). The 1st and 2nd rows show macroscopic findings of each case. The 3rd to 11th rows show microscopic findings of each case. NA, not available. Case 1: (a) The brain is mildly atrophic in the frontal and temporal lobes. (b) In the cerebral cortices, neuronal loss and gliosis are noted (HE). (c) PrP‐plaques in the temporal cortex (arrows, HE). (d) PrP‐plaques in the frontal cortex, particularly along the deep cortical layers (3F4‐immunostain). (e) PrP‐plaques in the putamen. (3F4‐immunostain). (f) PrP‐plaques in the thalamus (3F4‐immunostain). (g) In the cerebellum, PrP‐plaques are absent. (3F4‐immunostain). (h) In the cerebral white matter, myelin is well‐preserved (KB). (i) The medullary pyramid shows myelin loss/pallor (KB). (j) The spinal cord shows myelin loss/pallor in the pyramidal tract (arrows, HE‐LFB). Case 2: (a) The brain is severely atrophic, especially in the frontal and temporal lobes. (b) On coronal sections, the cortical ribbon is thin, the cerebral white matter and corpus callosum are atrophic and discolored, and the lateral ventricle is dilated. (c) In the cerebral cortices, neuronal loss and gliosis are severe. A mild degree of spongiform change is also noted. (HE). (d) PrP‐plaques in the temporal cortex. (arrows, HE). (e) PrP‐plaques in the frontal cortex, particularly along the deep cortical layers (3F4‐immunostain). (f) PrP‐plaques in the putamen (3F4‐immunostain). (g) PrP‐plaques in the thalamus (3F4‐immunostain). (h) In the cerebellum, a number of PrP‐plaques are present (3F4‐immunostain). (i) The cerebral white matter shows myelin loss/pallor (KB). (j) The medullary pyramid shows myelin loss/pallor (KB). (k) The spinal cord shows marked myelin loss/pallor in the pyramidal tract (arrows) and the posterior column (arrowheads) (KB). Case 3: (I) The brain is mildly atrophic in the frontal and temporal lobes. (II) On coronal sections, the gyri are mildly wide and the lateral ventricle is mildly dilated. (III) The tissue injuries in the cerebral cortices, including neuronal loss and gliosis, are minimal except for the presence of PrP‐plaques (arrows) (HE). (IV) A PrP‐plaque in the temporal cortex (arrow, HE). (V) PrP‐plaques in the frontal cortex, particularly along the deep cortical layers (3F4‐immunostain). (VI) PrP‐plaques in the putamen (3F4‐immunostain). (VII) PrP‐plaques in the thalamus (3F4‐immunostain). (VIII) In the cerebellum, PrP‐plaques are absent (3F4‐immunostain). (IX) The cerebral white matter shows mild myelin loss/pallor (KB). (X) In the medullary pyramid, myelin is well‐preserved (KB)

Figure 3

Case 1: (a–c, d–f) The distribution of PrP (a, d), p‐tau (b, e), and Aβ (c, f) in the temporal cortex (a–c) and hippocampus (d–f) is shown. The photos are taken from an identical area for a–c and d–f. P‐tau (b&e, AT8‐immunostain) seems considerably overlapped with PrP (a&d, 3F4‐immunostain), whereas Aβ (c&f, 4G8‐immunostain) is completely absent (Original magnification: a–c, ×40; d–f, ×20). (g) P‐tau‐positive dystrophic neurites (DNs) are aggregated around a PrP‐plaque (AT8‐immunostain, temporal cortex, ×600). (h) A fraction of DNs are argyrophilic (Gallyas silver stain, temporal cortex, ×600). (i) By double‐immunostaining with AT8 and PrP‐N, the Colocalization of p‐tau with PrP‐plaques is confirmed (p‐tau, red; PrP, brown. Occipital cortex, ×600)

Figure 4

Case 2: (a–c, d–f) The distribution of PrP (a, d), p‐tau (b, e), and Aβ (c, f) in the temporal cortex (a–c) and hippocampus (CA1 to subiculum, d–f) is shown. The photos are taken from an identical area for a–c and d–f. In the temporal cortex (a–c), p‐tau (b, AT8‐immunostain) and Aβ (c, 4G8‐immunostain) seem considerably overlapped with PrP (a, 3F4‐immunostain). Notably, most deposits of Aβ have an immuno‐negative central core (arrows, c). In the hippocampus (d–f), p‐tau (e, AT8‐immunostain) seems considerably overlapped with PrP (d, 3F4‐immunostai), whereas Aβ (f, 4G8‐immunostain) is totally absent. (Original magnification: a–c, ×40; d–f, ×40). (g) P‐tau‐positive dystrophic neurites (DNs) around PrP‐plaques (arrows), neurofibrillary tangles (arrowheads), and neuropil threads are commonly seen (AT8‐immunostain, temporal cortex, ×400). (h) A small fraction of DNs around PrP‐plaques are argyrophilic (Gallyas silver stain, frontal cortex, x600). (i) By double‐immunostaining with AT8 and PrP‐N, the colocalization of p‐tau with PrP‐plaques is confirmed. (p‐tau, red; PrP, brown. Temporal cortex, x400). (j) By double‐immunostaining with 4G8 and PrP‐N, the deposition of Aβ around PrP‐plaques is confirmed. Note that most Aβ is colocalized with PrP. (Aβ, red; PrP, brown. Temporal cortex, ×200). (k) By triple‐immunostaining with AT8, 4G8, and PrP‐N, the colocalization of p‐tau, Aβ, and PrP is confirmed (p‐tau, red; Aβ, brown; PrP, green. Temporal cortex, ×600). (l) By triple‐immunostaining with AT8, 4G8 and PrP‐N, it is also shown that PrP, with or without p‐tau, can be present without Aβ (arrows); on the other hand, Aβ, with or without p‐tau, cannot be present without PrP (arrowheads), suggesting that PrP deposition is likely a precursor event to Aβ deposition. (p‐tau, red; Aβ, brown; PrP, green. Temporal cortex, ×600)

Figure 5

Case 3: (a) Although minimal, p‐tau associated with PrP‐plaques is identified. (AT8‐immunostain, frontal cortex, original magnification ×600). (b) By double‐immunostaining with AT8 and PrP‐N, the colocalization of p‐tau with PrP‐plaques is confirmed (p‐tau, red; PrP, brown. Temporal cortex, ×400)

Figure 6

In all cases, both three repeat tau (RD3, a–c) and four repeat tau (RD4, d–f) are associated with PrP–plaques. (RD3‐ & RD4‐immunostain, original magnification: a&d, c&f ×600; b&e ×400)