Hippocampal synaptic alterations associated with tau pathology in primary age-related tauopathy

Abstract

Primary age-related tauopathy (PART) is characterized by aggregation of tau in the mesial temporal lobe in older individuals. High pathologic tau stage (Braak stage) or a high burden of hippocampal tau pathology has been associated with cognitive impairment in PART. However, the potential underlying mechanisms are not well understood. Cognitive impairment in many neurodegenerative diseases correlates with synaptic loss, raising the question of whether synaptic loss also occurs in PART. To address this, we investigated synaptic changes associated with tau Braak stage and high tau pathology burden in PART using synaptophysin and phospho-tau immunofluorescence. We compared 12 cases of definite PART with 6 controls and 6 Alzheimer disease cases. In this study, the hippocampal CA2 region showed loss of synaptophysin puncta and intensity in cases of PART with either a high stage (Braak IV) or a high burden of neuritic tau pathology. There was also loss of synaptophysin intensity in CA3 associated with a high stage or high burden of tau pathology. Loss of synaptophysin was present in Alzheimer disease, but the pattern appeared distinct. These novel findings suggest the presence of synaptic loss associated with either a high hippocampal tau burden or a Braak stage IV in PART.

Keywords: Aging; Neurodegeneration; Primary age-related tauopathy (PART); Synapses.

Figure 1.

Loss of synaptophysin in CA2 with Braak Stage IV in PART. (A) Immunostaining for synaptophysin and phospho-tau in CA2 of the hippocampus in a control, Braak IV PART, and high-level (Braak VI) AD. Note the low synaptophysin signal in the PART image compared to control and AD images, though the tau pathology is increased in AD compared to PART in the same region (blue arrows). Quantification of synaptophysin puncta (B) and intensity (C) by Braak stage in PART. Quantification of synaptophysin puncta (D) and intensity (E) in Alzheimer disease. Scale bars are 10 µm. Acquisition and display settings are standard across all images. Graphs show average value per region per case, with statistics shown from mixed-effects linear model. A significant interaction term between disease and region is noted by “:”, that is Braak IV:CA2 denotes a significant interaction of Braak IV stage with synaptophysin in the CA2 region. AD, Alzheimer disease; DG, dentate gyrus; pTau, phosphorylated tau.

Figure 2.

Neuritic tau pathology by Braak stage and with aging. (A) Quantification of phosphorylated tau volume by region and disease. (B) Age was not associated with Braak score in PART (p = 0.64, 1-way ANOVA). (C) Association of neuritic tau score with age in PART (p = 0.046, simple linear regression, shade is 95% confidence interval). AD, Alzheimer disease; IML, inner molecular layer of the dentate gyrus; OML, outer molecular layer of the dentate gyrus.

Figure 3.

Loss of synaptophysin with high neuritic tau burden in PART. (A) Hippocampal neuritic tau score used to divide PART cases into high and low tau burden (line is threshold between high and low tau scores). Quantification of synaptophysin puncta (B) and intensity (C) by tau burden in PART. Graphs show average value per region per case, with statistics shown from mixed-effects linear model. A significant interaction term between disease and region is noted by “:”, that is H Tau:CA2 denotes a significant interaction of high neuritic tau burden with synaptophysin in the CA2 region. AD, Alzheimer disease; DG, dentate gyrus; H Tau, high neuritic tau score; L Tau, low neuritic tau score; PART, primary age-related tauopathy.