The Amygdala as a Locus of Pathologic Misfolding in Neurodegenerative Diseases

Abstract

Over the course of most common neurodegenerative diseases the amygdala accumulates pathologically misfolded proteins. Misfolding of 1 protein in aged brains often is accompanied by the misfolding of other proteins, suggesting synergistic mechanisms. The multiplicity of pathogenic processes in human amygdalae has potentially important implications for the pathogenesis of Alzheimer disease, Lewy body diseases, chronic traumatic encephalopathy, primary age-related tauopathy, and hippocampal sclerosis, and for the biomarkers used to diagnose those diseases. Converging data indicate that the amygdala may represent a preferential locus for a pivotal transition from a relatively benign clinical condition to a more aggressive disease wherein multiple protein species are misfolded. Thus, understanding of amygdalar pathobiology may yield insights relevant to diagnoses and therapies; it is, however, a complex and imperfectly defined brain region. Here, we review aspects of amygdalar anatomy, connectivity, vasculature, and pathologic involvement in neurodegenerative diseases with supporting data from the University of Kentucky Alzheimer's Disease Center autopsy cohort. Immunohistochemical staining of amygdalae for Aβ, Tau, α-synuclein, and TDP-43 highlight the often-coexisting pathologies. We suggest that the amygdala may represent an "incubator" for misfolded proteins and that it is possible that misfolded amygdalar protein species are yet to be discovered.

Brain Imaging of Alzheimer Dementia Patients and Elderly Controls with 18F-MK-6240, a PET Tracer Targeting Neurofibrillary Tangles

“…A second AD subject (subject 6) exhibited only limited medial temporal and amygdala tracer retention despite significant clinical impairment (MMSE 11), indicating a discordance between clinical stage and expected 18 F-MK-6240 signal based on presumptive Braak staging. The high signal localized to the amygdala is not unexpected, with reports showing the presence of NFTs in amygdala in early-to-late stages of AD and that its signal magnitude could even be higher than in cortical regions (21,22). However, because only a small number of subjects were included in this study, conclusions on the specificity and sensitivity of 18 F-MK-6240 as a function of disease stage and neuropathologic diagnosis cannot be drawn.…”

Chronic corticosterone enhancement aggravates alpha-synuclein brain spreading pathology and substantia nigra neurodegeneration in mice

“…A high level of α-Syn pathology in the amygdala has been reported in patients suffering from PD and other neurodegenerative diseases 21 , as well as in several α-Syn pathology spreading models 27,28,30,33 . The amygdala is importantly involved in emotional behavior and depression in general 19 and in PD in particular 51 .…”

“…The involvement of the amygdala in stress effects, mood, emotion and reward behaviors is well-established 18,19 , and of interest also in the context of PD. Thus, the amygdala is particularly prone to the formation of α-Syn pathology (LBs in PD-patients and LB-like pathology in many animal models) 20,21 , which occurs there as early as α-Syn pathology is observed in the substantia nigra.…”

Amygdala: Neuroanatomical and Morphophysiological Features in Terms of Neurological and Neurodegenerative Diseases

“…The basolateral nuclei consist of the lateral (which is the largest in human brain and usually asymmetric) basal and accessory nuclei, and each of them are subdivided into other nuclei (Table 1). These nuclei receive signals from the cortex, thalamus and hippocampus [1,4,5]. The amygdala can be divided into the superficial region and transition zone with the entorhinal cortex.…”