Alzheimer's Dementia︱ A new non-human primate model of Alzheimer's disease: the rhesus monkey

And using rigorous academic and logical thinking to explore the mysteries of neuroscience, written by Wang Sizhen, edited by Wang Sizhen.
Alzheimer’s disease (AD), commonly known as Alzheimer’s disease, is one of the most common nerves that occur in the elderly.
Degenerative diseases, with insidious onset and chronic progressive course [1].

There is currently no effective treatment.

With the increase of the global elderly population, the incidence of AD is also getting higher and higher.

The main pathological features of AD are cerebral cortex atrophy, accompanied by β-amyloid (Aβ) deposition, neurofibrillary tangles, a reduction in the number of a large number of memory neurons, and the formation of senile plaques [2].

 In recent years, we have gained a deep understanding of the pathological events behind AD.
However, it is extremely difficult to translate research results, especially the successful translation of research results from rodent models (mouse and rat) into clinical applications.
Effective human treatment methods are extremely challenging [3-4].

Almost all clinical trials have failed.

Therefore, it is important to find animal models (such as non-human primates) that are more consistent with the pathogenesis of the disease.

 Non-human primates, such as rhesus monkeys, macaques, great apes, chimpanzees, macaques, etc.
, are evolutionarily closer to humans, and are also very similar to the occurrence and development of human AD pathology [5-8].

However, most non-human primate models can only present advanced AD pathology.
For the concept of "early detection, early prevention, and early treatment" of the disease, it is necessary to establish a model that can objectively present the early stage of AD A model that objectively reflects the occurrence and development of early AD pathology.

 On March 18, 2021, the research group of Professor John H.
Morrison of the California National Primate Research Center at the University of California, Davis, published a titled A novel tau-based rhesus monkey model of Alzheimer's pathogenesis on Alzheimer's and Dementia The latest research paper reported on a rhesus monkey model that can reflect the pathogenesis and development of early AD.
With age, the monkey model exhibits similar tau pathology and neuroinflammation processes that are similar to humans.

 First, the researchers used an adeno-associated virus (AAV) recombinant vector to unilaterally infuse the entorhinal cortex of adult rhesus monkeys (10-15 years old) with two tau mutants (P301L and S320F), both of which can cause Pathology of tau protein disease [9].

The results showed that compared with the control group (contralateral side) and with age, the core markers of AD, such as neurofilament light chain, total and phosphorylated tau protein, can be detected in the cerebrospinal fluid and plasma of rhesus monkeys.
The levels of myeloid cell trigger receptor-2 (TREM2) and pro-inflammatory cytokines increased, but the level of β-amyloid protein did not change (Figure 1).

At the same time, immunofluorescence histochemistry experiments and confocal microscopy observations showed that tau protein pathological changes can be clearly observed in the hippocampus of rhesus monkeys injected with tau mutants, that is, the spread and aggregation of misfolded tau, which is the same as that observed in the hippocampus of AD patients The early events of AD are similar (Figure 2).

Figure 1 Rhesus monkeys treated with AAV-mutant tau have obvious AD pathological features in the entorhinal cortex (picture quoted from: Beckman D, Chakrabarty P, Ott S, et al.
.
Alzheimer's Dement.
2021;1-13) Figure 2 Tau protein pathological changes can be clearly observed in the hippocampus of rhesus monkeys treated with AAV-mutant tau (picture quoted from: Beckman D, Chakrabarty P, Ott S, et al.
.
Alzheimer's Dement.
2021; 1-13).
More and more evidences show that glial cells and neuroinflammation play an important role in neurodegenerative diseases such as AD [10].

Normal microglia and astrocytes are usually involved in the removal of pathological proteins, and these glial cells in the activated state can promote the spread of pathological proteins and increase nerve promotion [11].

Here, the researchers found that in the hippocampus of rhesus monkeys injected with tau mutants, the number of reactive (i.
e.
, activating) microglia increased significantly, and they interacted closely with tau pathological neurons This means that the spread of misfolded tau protein in the hippocampus can cause a wide range of microglia responses (Figure 3).

Of course, the author has also observed the response of reactive astrocytes to tau pathology, but their interaction with pathological neurons is weak (Figure 3).

Figure 3 Rhesus monkeys treated with AAV-mutant tau showed significant inflammation in the hippocampus (picture quoted from: Beckman D, Chakrabarty P, Ott S, et al.
Alzheimer's Dement.
2021;1-13) Figure 4 Tau protein Different subtypes and post-translational modifications (picture source: C.
-W.
Chang et al.
, Science 2021; 371: eabb8255) [12] tau protein has different splicing subtypes, the two common subtypes are 3R and 4R (Figure 4), these different subtypes can cause different or the same tau protein disease pathology.

The 3R subtype is not expressed in the adult brain of rodents (mouse and rat), while both subtypes are expressed in the brain of rhesus monkeys, which is similar to humans.

The author used the AAV vector to inject the 4R subtype (exogenous) to study the role of the 3R subtype (endogenous) in the transmission of misfolded tau in vivo.

The results showed that the 4R subtype in the entorhinal cortex has a common site with tau pathological neurons and reactive microglia, while in the hippocampus, on the contrary, the 3R subtype is associated with tau pathological neurons and reactive microglia.
Microglia have common sites (Figure 5).

This potentially indicates that exogenous injection of tau mutants cannot induce the expression of the 3R and 4R subtypes in microglia in monkeys, but tau does exist in microglia, because these microglia are phagocytosed Tau pathological neurons.

Figure 5 Tau subtype 4R (exogenous) combined with tau subtype 3R (endogenous) to spread tau pathology in a prion-like manner (picture quoted from: Beckman D, Chakrabarty P, Ott S, et al.
.
Alzheimer's Dement.
2021 ;1-13) In addition, the author also found that in rhesus monkeys entorhinal cortex and brain regions other than hippocampus, especially the retrosplenial cortex and visual brain regions (V4 and V1), there are similar tau proteins.
The pathology changes in time and space, and the tau protein seeds spread and multiply in a prion-like manner (Figure 6).

Figure 6 Spatiotemporal process of misfolded tau protein in the brain of rhesus monkeys (picture quoted from: Beckman D, Chakrabarty P, Ott S, et al.
.
Alzheimer's Dement.
2021; 1-13) Conclusion and discussion of this study The work proposes a promising non-human primate model of the early stage of AD disease characterized by tau protein pathology-the rhesus monkey model, and rodent models (mice and rats).
) Comparison: 1.
Non-human primate animal models (such as the rhesus monkey model) are more similar to human neurodegenerative diseases (such as AD), especially in the early stages of the disease.

 2.
The rhesus monkey model, of course, also includes other non-human primate animal models, and also provides a more objective and true basis for the research and treatment of neurodegenerative diseases such as AD.

 3.
Gender, age, and other diseases such as diabetes and hypertension play an important role in the pathogenesis of neurodegenerative diseases such as AD.
Non-human primate models also serve to assess these coexisting risk factors in neurodegenerative diseases What role to play provides opportunities.

 4.
In the study, although it is not clear whether rhesus monkeys treated with AAV-mutant tau will show all the symptoms of AD, including severe cognitive impairment, in short, this work is the next step for testing to target tau Protein has laid the foundation for the treatment of AD patients.

Original link: https://doi.
org/10.
1002/alz.
12318 Recommended high-quality scientific research training courses [1] Medicine plus patch clamp and optogenetics and calcium imaging technology seminar (April 24-25, 2 days 1 night )【2】Online︱Single Cell Sequencing Data Analysis and Research Ideas Seminar (January 16-17, 21) (courses can be booked from April to May 2021) References (slide up and down to view)【1】2020 Alzheimer's disease facts and figures.
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Chang et al.
, Science 2021; 371: eabb8255 plate making︱ End of this articleA nonhuman primate model of early Alzheimer's disease pathologic change: Implications for disease pathogenesis.
Alzheimer's.
Dement.
2019;15:93-105.
[8] Paspalas CD, Carlyle BC, Leslie S, et al.
The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.
Alzheimer's Dement.
2018:680-691.
【9】Koller EJ, Gonzalez De La, Cruz E, et al.
Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.
Hum Mol Genet .
2019;28(19):3255-3269.
【10】Ransohoff RM.
How neuroinflammation contributes to neurodegeneration.
Science.
2016;353(6301):777-783.
【11】Fakhoury M.
Microglia and astrocytes in Alzheimer's disease: implications for therapy.
Curr Neuropharmacol.
2017;16(5):508-518【12】C.
-W.
Chang et al.
, Science 2021; 371: eabb8255 plate making ︱ Wang Sizhen end of this articleA nonhuman primate model of early Alzheimer's disease pathologic change: Implications for disease pathogenesis.
Alzheimer's.
Dement.
2019;15:93-105.
[8] Paspalas CD, Carlyle BC, Leslie S, et al.
The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.
Alzheimer's Dement.
2018:680-691.
【9】Koller EJ, Gonzalez De La, Cruz E, et al.
Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.
Hum Mol Genet .
2019;28(19):3255-3269.
【10】Ransohoff RM.
How neuroinflammation contributes to neurodegeneration.
Science.
2016;353(6301):777-783.
【11】Fakhoury M.
Microglia and astrocytes in Alzheimer's disease: implications for therapy.
Curr Neuropharmacol.
2017;16(5):508-518【12】C.
-W.
Chang et al.
, Science 2021; 371: eabb8255 plate making ︱ Wang Sizhen end of this articleImplications for disease pathogenesis.
Alzheimer's.
Dement.
2019;15:93-105.
【8】Paspalas CD, Carlyle BC, Leslie S, et al.
The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.
Alzheimer's Dement.
2018:680-691.
【9】Koller EJ, Gonzalez De La, Cruz E, et al.
Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.
Hum Mol Genet.
2019;28(19):3255-3269 .
【10】Ransohoff RM.
How neuroinflammation contributes to neurodegeneration.
Science.
2016;353(6301):777-783.
【11】Fakhoury M.
Microglia and astrocytes in Alzheimer's disease: implications for therapy.
Curr Neuropharmacol.
2017;16( 5): 508-518 [12] C.
-W.
Chang et al.
, Science 2021; 371: eabb8255 plate making︱ Wang Sizhen end of this articleImplications for disease pathogenesis.
Alzheimer's.
Dement.
2019;15:93-105.
[8]Paspalas CD, Carlyle BC, Leslie S, et al.
The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.
Alzheimer's Dement.
2018:680-691.
【9】Koller EJ, Gonzalez De La, Cruz E, et al.
Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.
Hum Mol Genet.
2019;28(19):3255-3269 .
【10】Ransohoff RM.
How neuroinflammation contributes to neurodegeneration.
Science.
2016;353(6301):777-783.
【11】Fakhoury M.
Microglia and astrocytes in Alzheimer's disease: implications for therapy.
Curr Neuropharmacol.
2017;16( 5): 508-518 [12] C.
-W.
Chang et al.
, Science 2021; 371: eabb8255 plate making︱ Wang Sizhen end of this articleThe aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.
Alzheimer's Dement.
2018:680-691.
【9】Koller EJ, Gonzalez De La, Cruz E, et al.
Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.
Hum Mol Genet.
2019;28(19):3255-3269.
【10】Ransohoff RM.
How neuroinflammation contributes to neurodegeneration.
Science.
2016;353(6301):777-783.
【11】Fakhoury M.
Microglia and astrocytes in Alzheimer's disease: implications for therapy.
Curr Neuropharmacol.
2017;16(5):508-518【12】C.
-W.
Chang et al.
, Science 2021; 371: eabb8255 plate making︱ End of this articleThe aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.
Alzheimer's Dement.
2018:680-691.
【9】Koller EJ, Gonzalez De La, Cruz E, et al.
Combining P301L and S320F tau variants produces a novel accelerated model of tauopathy.
Hum Mol Genet.
2019;28(19):3255-3269.
【10】Ransohoff RM.
How neuroinflammation contributes to neurodegeneration.
Science.
2016;353(6301):777-783.
【11】Fakhoury M.
Microglia and astrocytes in Alzheimer's disease: implications for therapy.
Curr Neuropharmacol.
2017;16(5):508-518【12】C.
-W.
Chang et al.
, Science 2021; 371: eabb8255 plate making︱ End of this article[10] Ransohoff RM.
How neuroinflammation contributes to neurodegeneration.
Science.
2016;353(6301):777-783.
[11] Fakhoury M.
Microglia and astrocytes in Alzheimer's disease: implications for therapy.
Curr Neuropharmacol.
2017;16(5 ):508-518【12】C.
-W.
Chang et al.
, Science 2021; 371: eabb8255 plate making ︱ Wang Sizhen end of this article[10] Ransohoff RM.
How neuroinflammation contributes to neurodegeneration.
Science.
2016;353(6301):777-783.
[11] Fakhoury M.
Microglia and astrocytes in Alzheimer's disease: implications for therapy.
Curr Neuropharmacol.
2017;16(5 ):508-518【12】C.
-W.
Chang et al.
, Science 2021; 371: eabb8255 plate making ︱ Wang Sizhen end of this article