Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi

Abstract

Introduction: Alzheimer's disease (AD), primary age-related tauopathy (PART), and chronic traumatic encephalopathy (CTE) all feature hyperphosphorylated tau (p-tau)-immunoreactive neurofibrillary degeneration, but differ in neuroanatomical distribution and progression of neurofibrillary degeneration and amyloid beta (Aβ) deposition.

Methods: We used Nanostring GeoMx Digital Spatial Profiling to compare the expression of 70 proteins in neurofibrillary tangle (NFT)-bearing and non-NFT-bearing neurons in hippocampal CA1, CA2, and CA4 subregions and entorhinal cortex of cases with autopsy-confirmed AD (n = 8), PART (n = 7), and CTE (n = 5).

Results: There were numerous subregion-specific differences related to Aβ processing, autophagy/proteostasis, inflammation, gliosis, oxidative stress, neuronal/synaptic integrity, and p-tau epitopes among these different disorders.

Discussion: These results suggest that there are subregion-specific proteomic differences among the neurons of these disorders, which appear to be influenced to a large degree by the presence of hippocampal Aβ. These proteomic differences may play a role in the differing hippocampal p-tau distribution and pathogenesis of these disorders.

Highlights: Alzheimer's disease neuropathologic change (ADNC), possible primary age-related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) can be differentiated based on the proteomic composition of their neurofibrillary tangle (NFT)- and non-NFT-bearing neurons. The proteome of these NFT- and non-NFT-bearing neurons is largely correlated with the presence or absence of amyloid beta (Aβ). Neurons in CTE and definite PART (Aβ-independent pathologies) share numerous proteomic similarities that distinguish them from ADNC and possible PART (Aβ-positive pathologies).

Keywords: Alzheimer's disease neuropathologic change; aging; autophagy; chronic traumatic encephalopathy; cognitive reserve; neurodegeneration; oxidative stress; primary age‐related tauopathy; resilience; resistance; synapse loss; synapses; tauopathy.

FIGURE 1

Representative paired phosphorylated tau (p‐tau; AT8) immunohistochemical stains and immunofluorescent stains demonstrating p‐tau and amyloid beta (Aβ) pathology in overview hippocampal sections, the entorhinal cortex, CA1 subregion, CA2 subregion, and CA4 subregion in representative cases of Alzheimer's disease neuropathologic change (ADNC), definite primary age‐related tauopathy (PART), and chronic traumatic encephalopathy (CTE). Overview panel scalebars = 2 mm, subregion panel scalebars = 100 µm.

FIGURE 2

Principal component analysis (PCA) of (A‐B) neurofibrillary tangle (NFT)–bearing neurons, (C‐D) non–NFT‐bearing neurons, and (E‐F) all neurons in cases of Alzheimer's disease neuropathologic change (ADNC), possible primary age‐related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE).

FIGURE 3

Correlation analysis examining (A) the relationship between the level of each quantified protein and the presence of each neurodegenerative pathology (ADNC, possible PART, definite PART, and CTE) as well as (B) the relationship between the level of protein expression and the presence of Aβ (only significant interactions displayed). Aβ, amyloid beta; ADNC, Alzheimer's disease neuropathologic change; CTE, chronic traumatic encephalopathy; PART, possible primary age‐related tauopathy.

FIGURE 4

Significant differences in levels of phosphorylated tau (p‐tau) epitopes in neurofibrillary tangle (NFT)‐bearing neurons and non–NFT‐bearing neurons (and their immediate microenvironments) between subjects with Alzheimer's disease neuropathologic change (ADNC), possible primary age‐related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) in each hippocampal subregion evaluated. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001.

FIGURE 5

Significant differences in protein levels in neurofibrillary tangle (NFT)‐bearing neurons (and their immediate microenvironments) between subjects with Alzheimer's disease neuropathologic change (ADNC), possible primary age‐related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) in each hippocampal subregion evaluated. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001.

FIGURE 6

Differences in protein levels in non‐neurofibrillary tangle (NFT)‐bearing neurons (and their immediate microenvironments) between subjects with Alzheimer's disease neuropathologic change (ADNC), possible primary age‐related tauopathy (PART), definite PART, and chronic traumatic encephalopathy (CTE) in each hippocampal subregion evaluated. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001.