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Page 2 of 13 Li et al. Ageing Neur Dis 2022;2:12 https://dx.doi.org/10.20517/and.2022.14

Keywords: Neurodegeneration, non-human primate, gene editing

INTRODUCTION
Neurodegenerative diseases (NDs) represent a group of devastating neurological disorders, including
Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s
disease (HD). NDs are characterized by progressive loss of specific populations of neurons in the affected
brain regions. NDs always manifest clinical symptoms in old age. As the life span and global population
increase, the number of ND patients is expected to rapidly rise in the coming decades .
[1-4]

At present, no therapy can reverse, halt, or slow NDs, although a lot of progress has been made in the past
decades. One of the important reasons for the failure to effectively treat NDs is that the pathogenesis of NDs
is still an enigma. Although most (> 90%) NDs are sporadic, small populations of familial NDs are found to
carry genetic mutations. Identification of these genetic defects enabled the generation of gene-modified
animals, which provide important animal models for us to investigate the pathogenesis of NDs . Of these
[5,6]
animal models, rodents are widely used and serve as essential animal models for investigating almost all
types of NDs, largely because of their small size, fast breeding, and short generation time, as well as the
available embryonic stem cells (ESC) that allow for genetically modifying endogenous rodent genes
efficiently. As a result, several ND rodent models have been created, and investigation of these animal
models has generated a wealth of information regarding the pathological changes and mechanisms of NDs.
Although most rodent models can recapitulate the important pathological hallmarks of NDs, overt neuronal
loss is often missed , making it difficult to use rodent models to rigorously evaluate therapeutic effects on
[7]
neurodegeneration. In line with this scenario, most therapeutic trials based on findings from rodent NDs
models have failed clinically . NHPs are closer to humans than other species of animals, especially in their
[8]
brain structure and function, as well as the aging process [9,10] . Recently, several NHP ND models have been
generated and provided new insights into ND pathogenesis. Here, we review the strengths of NHPs for ND
investigation, highlight new pathogenic insights offered by NHP models of NDs with a focus on AD, PD,
and ALS, and discuss challenges and perspectives for future studies.

UNIQUE ADVANTAGES OF NHPS FOR ND INVESTIGATION
The brain is the most complex and delicate organ of mammals, responsible for information reception,
procession, decision making, and organism behavior. During evolutionary progress, primates developed a
[11]
sophisticated central never system (CNS), leading to the most intelligent human being . Laboratory NHPs
primarily consist of cynomolgus (Macaca fascicularis), rhesus (Macaca mulatta), and marmoset (Callithrix
jacchus). The first two are old world monkeys belonging to the macaque genus, descended from the same
ancestor 1.8 million years ago , and share the same ancestors with humans around 30 million years ago,
[12]
while the mouse was divergent from humans 70 million years ago . Macaque monkeys are more proximal
[13]
to humans phylogenetically and more widely used in biomedical research due to their unparalleled high
level of similarity with humans in the following important aspects.

First, there is a tremendous similarity in brain structure between macaque monkeys and humans. Human
and monkey brains are full of gyrus and sulci at the outer surface, whereas rodent brains lack the important
feature of gyrification [14-16] . While there are several differences in brain anatomy between rodents and
humans, these differences do not exist in monkeys when compared with humans. For example, the
striatum, which is particularly affected in Huntington’s disease, is divided into caudate and putamen in both
monkey and human brains but lacks these two distinct parts in rodent brains [17-20] . The similar brain
anatomy and structure in humans and non-human primates are likely due to the similar timelines for brain