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Li et al. Ageing Neur Dis 2022;2:12 https://dx.doi.org/10.20517/and.2022.14 Page 3 of 13

development. For example, the complete formation of CNS in humans and macaque monkeys before birth
requires about 280 and 160 days, respectively, which is significantly different from the rapid formation of
the mouse brain in 18 days [Table 1]. In addition, the postnatal primate (macaques and human) brain takes
[21]
several years to reach maturation, while the rodent brain needs less than half a year . Adult neurogenesis is
kept in the subventricular zone and subgranular zone of the hippocampus in mice throughout life, while it
is controversial in primates [22-24] .

Second, the composition and morphology of cell types in the human brain are more similar to those in the
monkey brain than in small animal brains [25-27] . Astrocytes and microglia collaborate to sustain brain
environment homeostasis, and they also play important roles in aging and neurodegeneration [28-30] . The
soma size and morphology of glial cells, as well as their ratio to neurons in mice, differ significantly from
those in the primate [31,32] . For example, astrocytes in the non-human primate brains develop more abundant
processes in the same manner as human astrocytes than those in the mouse brain [33-36] . Astrocytes are a core
element of the blood-brain barrier (BBB), which works at the interface of capillary blood vessels and
cerebral parenchyma, stringently regulating the materials exchange [37,38] . BBB breakdown is a hallmark event
in several degenerative diseases. Positron emission computed tomography (PET) radiotracers [39,40] and
recent adeno-associated virus (AAV)-mediated transgene [41,42] studies have revealed the special role of the
NHP BBB in expressing and distributing transgenes. Glial cells are essential for the survival of neurons by
both providing neurotrophic, nutritional, and structural support and removing toxic insults [43,44] . It has been
well documented that glial dysfunction plays a critical role in NDs [45-47] . Similarities in glial cells between
non-human primates and humans are obviously an advantage for NHP models of NDs.

Non-human primates also closely resemble many aspects of humans in genomic regulation, aging process,
metabolism, and physiology. The monkey genome holds more variations among individual alleles, offering
a more faithful genomic context to interrogate molecular pathogenesis. For example, genome-wide
association studies have established that the first genetic risk factor for AD is the APOE ε4 allele, which is
present in primates but absent in rodents [48,49] .

Non-human primates are particularly useful for examining behavioral abnormalities that also occur in NDs.
It is well known that depressive behavior and cognitive impairment are the common features of patients
with NDs. These phenotypes, which are hardly assessed in small animal models, can be evaluated in
monkeys using well-established behavioral assessments [50,51] .

NHP models of AD
AD is the most common neurodegenerative disease, the sixth leading cause of death, and 7%-8% of people
over age 65 have AD [52,53] . The typical clinical symptoms of AD consist of memory loss, cognitive
[54]
dysfunction, and mental as well as behavioral abnormalities . Extracellular senile amyloid plaques and
intracellular neurofibrillary tangles (NFTs) are two pathological hallmarks of AD. In addition, cerebral
amyloid angiopathy, demyelination, neuroinflammation, brain atrophy, and synaptic ion dyshomeostasis
are frequently detected in association with AD pathology . More than 90% of AD patients are sporadic
[55]
with amnesic manifestation in the mid-60s or later, while fewer than 10% of AD cases are familial form with
early-onset symptoms caused by genetic mutations in the amyloid precursor protein (APP), presenilin 1,
and presenilin 2 genes [56,57] . Based on these genetic findings, numerous transgenic mouse models expressing
[58]
familial mutations driven by various promoters have been created . However, although prominent Aβ
deposition can be seen, obvious Tau accumulation, the other pathological hallmark, is hardly seen in these
mouse models [59-61] . Further, these Aβ transgenic mouse models do not develop overt and robust
neurodegeneration as seen in patients with AD [62,63] . Because brain imaging data indicate that symptom