Spectrum of tau pathologies in Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominant disorder caused by a trinucleotide expansion in the huntingtin gene. Recently, a new role for tau has been implicated in the pathogenesis of HD, whereas others have argued that postmortem tau pathology findings are attributable to concurrent Alzheimer's disease pathology. The frequency of other well-defined common age-related tau pathologies in HD has not been examined in detail. In this single center, retrospective analysis, we screened seven cases of Huntington's disease (5 females, 2 males, age at death: 47-73 years) for neuronal and glial tau pathology using phospho-tau immunohistochemistry. All seven cases showed presence of neuronal tau pathology. Five cases met diagnostic criteria for primary age-related tauopathy (PART), with three cases classified as definite PART and two cases as possible PART, all with a Braak stage of I. One case was diagnosed with low level of Alzheimer's disease neuropathologic change. In the youngest case, rare perivascular aggregates of tau-positive neurons, astrocytes and processes were identified at sulcal depths, meeting current neuropathological criteria for stage 1 chronic traumatic encephalopathy (CTE). Although the patient had no history of playing contact sports, he experienced several falls, but no definitive concussions during his disease course. Three of the PART cases and the CTE-like case showed additional evidence of aging-related tau astrogliopathy. None of the cases showed significant tau pathology in the striatum. In conclusion, while we found evidence for tau hyperphosphorylation and aggregation in all seven of our HD cases, the tau pathology was readily classifiable into known diagnostic entities and most likely represents non-specific age- or perhaps trauma-related changes. As the tau pathology was very mild in all cases and not unexpected for a population of this age range, it does not appear that the underlying HD may have promoted or accelerated tau accumulation.

Figure 1.

HD-associated intranuclear inclusions are highlighted by immunohistochemical stains for (A) p62, (B) polyglutamine, (C, D) FUS, with diminished diffuse FUS nuclear reactivity in (C) and preserved nuclear FUS reactivity in (D) compared to non-inclusion bearing neurons.

Figure 2.

(A) Representative image of age-associated neuronal tau pathology, consisting of neurofibrillary tangles and neuropil threads in the entorhinal cortex. (B-E) Representative images of age-associated astrocytic tau pathologies, depicting examples of perivascular white matter (B), subpial (C), and subependymal (D) thorn-shaped astrocytes and rare granular/fuzzy cortical astrocytes (E). (F-I) CTE-like pathology in case 1, consisting of perivascular aggregates at a sulcal depth (F) associated with thorn-shaped astrocytes in the overlying subpial zone (G). H&E image of hemosiderin-containing glial scar in superficial entorhinal cortex (H) associated with thorn-shaped astrocytes in the overlying subpial zone (I). All images except H are labeled with pTau antibody PHF1.

Figure 3.

Minimal tau pathology is present in the striatum. (A-C) Rare neuropil threads, (D) a very rare pre-tangle and (E) a very rare thorn-shaped astrocyte are seen. No nuclear rods are identified in residual striatal neurons (F). Images A and E are labeled with pTau antibody PHF1, images B and D with pTau antibody CP13 and images C and E with phosphorylation-independent polyclonal tau antibody.

Figure 4.

Immunofluorescence staining for SFPQ (green) reveals strong nuclear neuronal reactivity in cortical sections (A), but variable nuclear reactivity in the striatum (B, C). SFPQ nuclear reactivity is diffuse and somewhat granular, but no intranuclear aggregates were identified. HD-associated intranuclear inclusions, highlighted by p62 (red) are seen in strongly (A, B) and weakly (C) SFPQ-positive cells.