Bearded capuchin monkeys as a model for Alzheimer's disease

Abstract

The absence of a natural animal model is one of the main challenges in Alzheimer's disease research. Despite the challenges of using nonhuman primates in studies, these animals can bridge mouse models and humans, as nonhuman primates are phylogenetically closer to humans and can spontaneously develop AD-type pathology. The capuchin monkey, a New World primate, has recently attracted attention due to its skill in creating and using instruments. We analyzed one capuchin brain using structural 7 T MRI and performed a neuropathological evaluation of three animals. Alzheimer-type pathology was found in the two of the capuchins. Widespread β-amyloid pathology was observed, mainly in focal deposits with variable morphology and a high density of mature plaques. Notably, plaque-associated dystrophic neurites associated with disruption of axonal transport and early cytoskeletal alteration were frequently found. Unlike in other species of New World monkeys, cerebral arterial angiopathy was not the predominant form of β-amyloid pathology. Additionally, abnormal aggregates of hyperphosphorylated tau, resembling neurofibrillary pathology, were observed in the temporal and frontal cortex. Astrocyte hypertrophy surrounding plaques was found, suggesting a neuroinflammatory response. These findings indicate that aged capuchin monkeys can spontaneously develop Alzheimer-type pathology, indicating that they may be an advantageous animal model for research in Alzheimer's disease.

Figure 1

Macroscopic images. (a) Superior, (b) inferior, and (c) lateral views of the three capuchin monkey brains showing cortical gyrification. (d) Coronal section of the hippocampus at the level of the lateral geniculate nucleus. Scale unit: centimeters.

Figure 2

7 T ex situ brain magnetic resonance image (MRI) of a 29-year-old capuchin monkey. (a) Axial brain 7 T MRI image showing cortical gyrification. (b) In a T2-weighted image obtained from a 7 T MRI of a coronal slice, cortical lamination of the frontal cortex (blue arrow) and connections between the caudate and putamen (orange arrow) were observed. The claustrum can also be well identified (green arrow). (c) A macroscopic coronal slice at the same level as in (b).

Figure 3

β-amyloid pathology was observed in the brains of 33-year-old (S2) and 29-year-old (S3) capuchins. Immunoreactive β-amyloid deposits in the frontal cortex (a) and temporal cortex (b). Plaques with amyloid cores (c,d) were also observed via hematoxylin–eosin staining (e,f). Focal β-amyloid deposits were observed as primitive (g) or mature plaques with different morphologies (h–l). β-Amyloid deposits in the meningeal and intracortical vessels were observed (m,n), and capillary involvement was observed (o,q). 4G8 antibody (a–d,g–q). Scale bars = 100 µm (a), 50 µm (b,m,n,o,q); 20 µm (c–i).

Figure 4

Dystrophic neurites, astrocytes, microglial changes, and age-related alterations were observed in capuchin monkeys. Abnormal neurites associated with plaques were identified via immunohistochemistry using antibodies against p62 (a–c) and neurofilament ((d); 2F11). In addition, immunohistochemical staining revealed hypertrophic astrocytes surrounding β-amyloid plaques ((e,f); GFAP) and microglial activation ((g,h); Iba1). Additionally, age-related alterations were observed via routine staining, specifically, (i) Marinesco bodies in neurons of the substantia nigra immunoreactive for the p62 antibody ((j); arrows) and (k) intracellular PAS-positive granular pigment (k,m). The PAS-positive pigment was β-amyloid; ((n); 4G8) immunoreactive. Scale bars: 20 µm  (a,c,d,g–n); 50 µm (b,e,f).

Figure 5

Hyperphosphorylated tau deposits are observed in the form of tau immunoreactive aggregates (AT8). (a) Surrounding the core of a classical neuritic plaque, (b–i) neurofibrillary pathology resembling pretangles and neurofibrillary tangles and neuropil threads. Scale bars: 20 µm (a,b,h,i); 50 µm (c,d,e,g), 100 µm (f).