Hippocampal Synaptic Alterations Associated with Tau Pathology in Primary Age-Related Tauopathy

Abstract

Primary Age-Related Tauopathy (PART) is characterized by the 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 have been associated with cognitive impairment in PART. However, the underlying mechanisms of cognitive impairment in PART are not well understood. Cognitive impairment in many neurodegenerative diseases correlates with synaptic loss, raising the question of whether synaptic loss occurs in PART. To address this, we investigated synaptic changes associated with tau Braak stage and a high tau pathology burden in PART using synaptophysin and phospho-tau immunofluorescence. We compared twelve cases of definite PART with six young controls and six Alzheimer's disease cases. In this study, we identified loss of synaptophysin puncta and intensity in the CA2 region of the hippocampus 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 signal was present in AD, but the pattern was distinct from that seen in PART. These novel findings suggest the presence of synaptic loss in PART associated with either a high hippocampal tau burden or a Braak stage IV. These synaptic changes raise the possibility that synaptic loss in PART could contribute to cognitive impairment, though future studies including cognitive assessments are needed to address this question.

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. Quantification of synaptophysin puncta (B) and intensity (C) by Braak stage in PART. Quantification of synaptophysin puncta (D) and intensity (E) in Alzheimer’s 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. AD, Alzheimer’s 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, one-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’s 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. AD, Alzheimer’s disease; DG, dentate gyrus; H Tau, high neuritic tau score; L Tau, low neuritic tau score; pTau, phosphorylated tau.