Pathological Markers of Alzheimer's Disease and Related Dementia in the Rhesus Macaque Amygdala.

Rhesus macaques develop amyloid-ß (Aß) plaques during old age, but it is unclear how extensively they express other pathological hallmarks of dementia. Here we used immunohistochemistry to examine expression of phosphorylated tau (pTau) protein and cytoplasmic inclusions of TAR DNA binding protein 43 kDa (TDP-43) within the amygdala of young and old males, and also in old surgically-menopausal females that were maintained on regular or obesogenic diets. Only one animal, a 23-year-old female, showed pTau expression and none showed TDP-43 inclusions. What genetic and/or environmental factors protect macaques from expressing more severe human neuro-pathologies remains an interesting unresolved question.

Mechanisms underlying TDP-43 pathology and neurodegeneration: An updated Mini-Review.

TAR DNA binding protein 43 kDa (TDP-43) plays an important role in several essential cell functions. However, TDP-43 dysfunction has been implicated in the development of various brain diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Recent investigations into the individual components of TDP-43 pathology show how broader TDP-43 dysfunction may precede these disease end states, and therefore could help to explain why TDP-43 dysfunction continues to be implicated in a rapidly expanding category of neurodegenerative diseases. The literature reviewed in this article suggests that dysregulation of TDP-43 initiated by some environmental and/or genetic insults can lead to a snowballing dysfunction across the cell, involving impaired gene expression, mRNA stability, as well as the function and coordination of those pathways directly regulated by TDP-43. Furthermore, the hallmarks of TDP-43 pathology, such as hyperphosphorylation and insoluble cytoplasmic accumulation of the protein may actually be artifacts of an upstream impairment in TDP-43's normal function. Overall, the present article summarizes current knowledge regarding TDP-43's normal and pathological cell functions and sheds light on possible mechanisms that underlie its causal role in neurodegeneration.

Effect of hormone replacement therapy on amyloid beta (Aß) plaque density in the rhesus macaque amygdala.

Background: Amyloid beta (Aß) plaque density was examined in the amygdala of rhesus macaques, to elucidate the influence of age, diet and hormonal environment. Methods: Luminex technology was used to measure cerebrospinal fluid (CSF) concentrations of Aß40 and Aß42 across three decades, while immunohistochemistry was used to examine Aß plaque density in the amygdala. Results: Aß40 was found to be the predominant isoform of Aß in the CSF, but neither Aß40 or Aß42 concentrations showed an age-related change, and the ratio of Aß42 to Aß40 showed only a marginal increase. Significantly fewer Aß plaques were detected in the amygdala of old ovariectomized animals if they received estradiol HRT (p < 0.001); similar results were obtained regardless of whether they had been maintained on a regular monkey chow for ∼48 months or on a high-fat, high-sugar, Western-style diet for ∼30 months. Conclusion: The results demonstrate that HRT involving estrogen can reduce Aß plaque load in a cognitive brain region of aged non-human primates. The results from this translational animal model may therefore have clinical relevance to the treatment of AD in post-menopausal women, whether used alone, or as a supplement to current pharmacological and monoclonal antibody-based interventions.