Abstract
Amyloid plaques and neurofibrillary tangles (NFTs) are hallmark lesions of Alzheimer’s disease (AD) related to β-amyloid (Aβ) deposition and intraneuronal phosphorylated tau (pTau) accumulation. Sortilin C-terminal fragments (shortened as “sorfra”) can deposit as senile plaque-like lesions within AD brains. The course and pattern of sorfra plaque formation relative to Aβ and pTau pathogenesis remain unknown. In the present study, cerebral and subcortical sections in postmortem human brains (n = 46) from aged and AD subjects were stained using multiple markers (6E10, β-secretase 1, pTau, and sortilin antibodies, as well as Bielschowsky silver stain). The course and pattern of sorfra plaque formation relative to Thal Aβ and Braak NFT pathogenic stages were determined. Sorfra plaques occurred in the temporal, inferior frontal and occipital neocortices in cases with Thal 1 and Braak III stages. They were also found additionally in the hippocampal formation, amygdala, and associative neocortex in cases with Thal 2–4 and Braak IV–V. Lastly, they were also found in the primary motor, somatosensory, and visual cortices in cases with Thal 4–5 and Braak VI. Unlike Aβ and pTau pathologies, sorfra plaques did not occur in subcortical structures in cases with Aβ/pTau lesions in Thal 3–5/Braak IV–VI stages. We establish here that sorfra plaques are essentially a cerebral proteopathy. We believe that the development of sorfra plaques in both cortical and hippocampal regions proceeds in a typical spatiotemporal pattern, and the stages of cerebral sorfra plaque formation partially overlap with that of Aβ and pTau pathologies.
Highlights
Senile plaque deposition and neurofibrillary tangle (NFT) formation are considered as the two primary neuropathological features in Alzheimer’s disease (AD); both were initially identified in human brains using classic histological preparations (Critchley, 1929; Oifa, 1973; García-Marín et al, 2007; Ohry and Buda, 2015)
Among the brains obtained from non-demented elderly in our brain bank during the past several years, a substantial number of cases were pathologically characteristic of Primary age-related tauopathy (PART) (Table 1), allowing us to investigate whether sorfra plaques could develop in the brains with tauopathy alone
The lack of Aβ plaque pathology was confirmed by the absence of BACE1-labeled dystrophic neurites across the cortical and hippocampal subregions, whereas the distinct BACE1 expression normally present at the mossy fiber terminals was clearly seen in CA3 and the hilus of dentate gyrus (DG) (Supplementary Figure S1)
Summary
Senile plaque deposition and neurofibrillary tangle (NFT) formation are considered as the two primary neuropathological features in Alzheimer’s disease (AD); both were initially identified in human brains using classic histological preparations (i.e., silver and tinctorial amyloid stains) (Critchley, 1929; Oifa, 1973; García-Marín et al, 2007; Ohry and Buda, 2015). The spatiotemporal patterns of amyloid and tangle formation have been established through the examination of postmortem brains from cognitively normal and demented human subjects and adapted into the National Institutes of Health (NIH) guidelines for AD diagnosis, and which serve as a foundation for antemortem clinicopathological investigations with novel Aβ and pTau imaging markers (Montine et al, 2012; Boluda et al, 2015; Johnson et al, 2016; Buckley et al, 2017; Grothe et al, 2017; Jack et al, 2018; Schwarz et al, 2018; Long and Holtzman, 2019; Mattsson et al, 2019). A simplified version is proposed, which combines the above into three stages, that is, entorhinal (including Braak stages I and II), limbic (III and IV), and isocortical (V and VI) stages (Serrano-Pozo et al, 2011, 2016)
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