Lack of limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathological changes in aged macaques with memory impairment

.Abstract

The neuropathological changes of limbic-predominant age-related TDP-43 encephalopathy (LATE) are frequent in the aged population and are now recognized as a cause of memory impairment. However, it remains unknown if this proteinopathy is also present in other primate species. We thus investigated the presence and distribution of TDP-43 pathology in the hippocampus and amygdala of 7 aged memory-impaired rhesus macaques (Macaca mulatta, 18–32 years old) from 2 different cohorts. While present in an FTLD-TDP case used as a positive control for immunostaining, we found no TDP-43 or phosphorylated TDP-43 immunoreactive neuronal cytoplasmic inclusion in the amygdala or the hippocampus of these aged animals (as well as in young and mature macaques used as negative controls). We concluded that LATE is probably a human-specific condition, such as many other proteinopathies, and does not participate in age-related memory impairment in non–human primates.

Introduction

Limbic-predominant age-related TDP-43 encephalopathy (LATE), and its underlying neuropathological changes (LATE-NC), are now recognized as a frequent proteinopathy in aged subjects (Nelson et al., 2019). LATE-NC are characterized by TAR DNA-binding protein 43 (TDP-43) inclusions primarily located in limbic regions (amygdala and hippocampus) that can be differentiated histologically from frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) (Robinson et al., 2020). While LATE-NC may be co-morbid with Alzheimer's disease (AD) neuropathological changes, they can also be present in isolation and are often suspected in clinical practice in patients with amnesic syndrome and normal AD biomarkers (Besser et al., 2020; Nag et al., 2017). Given the lack of specific TDP-43 biomarkers, this clinical situation is also referred to as Suspected non–Alzheimer disease Pathophysiology (SNAP) (Jack et al., 2016).

Behavioral changes, including memory impairment, have frequently been reported in aged non–human primates (NHPs) species. However, the causes of these age-related behavioral changes are poorly explained in NHPs, mainly because researchers failed to detect true extensive AD tau pathology with neurodegeneration in these animals (Walker and Jucker, 2017). This situation in NHPs mimics the neurologic concept of SNAP. Thus, we hypothesized that aged rhesus macaques, presenting with memory impairment but no AD pathologic changes, may exhibit some lesions reminiscent of LATE-NC.