AD ()

Alzheimer's disease - a common neurodegenerative disease

Alzheimer's disease (Alzheimer disease, AD) is a neurodegenerative disease that occurs mostly in the elderly, and was first discovered and named by German doctor Alois ALZHEIMER in 1907 [1]. According to statistics, there are more than 50 million AD patients in the world, and it is expected to increase to ≥152 million by the middle of the 21st century.

AD is a very complex neurodegenerative disease, the pathological mechanism has not yet been clarified, and there are several mainstream hypotheses. The cholinergic hypothesis believes that the degeneration of cholinergic neurons in the basal layer of the brain and the loss of cholinergic neurotransmission in the cerebral cortex lead to the decline of cognitive function in AD patients [3]. Enzyme inhibitors (donepezil, galantamine, rivastigmine) for the treatment of AD is based on this hypothesis. The amyloid cascade hypothesis holds that the pathogenesis of AD is due to abnormal Aβ amyloid production and aggregation in the brain, forming insoluble oligomers with neurotoxic effects [4]. Another hypothesis holds that the pathogenesis of AD is due to the dysfunction of phosphorylated tau protein (p-tau) in the subcortical and medial temporal limbic areas of the brain, and the aggregation of Aβ protein (β-amyloid, Aβ) accelerates p-tau Wide spread of protein-associated neurodegeneration [5].

In AD clinical research, common biomarkers can generally be classified into the following three categories [6-7]:

(1) Hippocampal volume determined by magnetic resonance imaging (MRI);
(2) Cerebrospinal fluid biomarkers: t-tau protein, p-tau protein and Aβ amyloid protein (Aβ protein composed of 40 or 42 amino acids, namely Aβ40, Aβ42);
(3) Aβ amyloid protein image in the brain measured by positron emission tomography (PET).

The main clinical manifestations of AD are the gradual decline of early memory and mild cognitive impairment, and the obvious decline of memory in the middle and late stages, as well as language and movement disorders and personality changes. The main hallmark pathological features of AD include the accumulation of extracellular β-amyloid protein in neurons to form senile plaques (senile plaques, SP), abnormal phosphorylation of tau protein to form neurofibrillary tangles (neurofibrillary tangles, NFT) and neuron loss. Therefore, according to its pathological characteristics, hypotheses related to the pathogenesis were put forward, including oxidative stress (oxidative stress, OS) damage, abnormal phosphorylation of tau protein, cholinergic damage, aluminum poisoning and Aβ toxicity, etc., and on the basis of related hypotheses Animal models of AD were established.

The first type of aging model is based on aging, and age is one of the important risk factors for the onset of AD. Animal models take advanced age as the basis of AD pathogenesis, which can be formed spontaneously. On the one hand, it conforms to the physiological characteristics of aging or aging, and on the other hand, it does not require human intervention, which reduces the errors caused by the participation of human factors, mainly including natural aging models and rapid aging models, and D-galactose (D-gal). Acute aging model, ozone damage aging model, thymic aging and other models.

The second type of model induced by various factors is based on the pathological hypothesis of AD disease, and various intervention methods are used to intervene experimental animals to prepare corresponding animal models. Different means are divided into physical injury, chemical injury, and diet-induced models. For example, physical injury represented by carotid artery ligation model, chemical injury represented by Aβ injection and ibotenic acid injection model, and food-induced model induced by high-fatfood.

The third type is based on genetic theory, modifying human or animal disease-related genes as the target gene, splicing a specific promoter and implanting it into animals (the most commonly used is mice, and a few are rats and fruit flies) , zebrafish) fertilized eggs. Then the fertilized eggs are introduced into pseudopregnant animals to stably inherit various transgenic models to replicate the specific pathological characteristics of AD: more common single transgenic models such as APP, PS-1, PS-2 and apoE4. In addition, there are also double/multiple transgenic models constructed on the basis of single transgenic models combined with other single transgenic models. For example, APP/PS double transgenic mice express Aβ faster and more stably to form the pathological characteristics of Aβ increase and aggregation. However, such models, like the APP model, cannot develop tau pathology. However, APP/Tau double transgenic mice can simultaneously develop Aβ plaque deposition and neurofibrillary tangles.

At present, there are many experimental animal models of AD commonly used, which exhibit different disease symptoms and pathological changes. Each animal model has its own strengths and weaknesses. Therefore, it is necessary to choose the corresponding model according to the principle of disease occurrence and the purpose of the experiment.

Literature citation
[1] ALZHEIMER A,STELZMANN RA,SCHNITZLEIN HN,MURTAGH FR. An English translation of Alzheimer′s 1907 paper,“Uber eine eigenartige Erkankung der Hirnrinde”［J］. Clin Anat,1995,8（6）：429-431.
[2] FLEMING R, ZEISEL J, BENNETT K. World Alzheimer Report 2020：design dignity dementia：dementia- related design and the built environment Volume 1［R/OL］. London,England：Alzheimer′s Disease International,2020［2020-09-16］. https：//www.alzint.org/about/dementia-facts-figures/.
[3] Hampel H, Mesulam MM, Cuello AC, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer's disease [ J]. Bra in, 2018, 141(7): 1917-1933.
[4] Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics J] . Science, 2002, 297(5580): 353356.
[5] Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders [J]. Nat Rev Neurosci, 2007, 8(9): 663672.
[6]Cummings J, Lee G, Ritter A, et al. Alzheimer's disease drug development pipeline: 2019 J. Alzheim- ers Dement (NY), 2019, 5(2): 72-93.
[7]Cummings J, Lee G, Ritter A, et al. Alzheimer's disease drug development pipeline: 2020 J. Alzheim- ers Dement (NY), 2020, 6(1): e12050.

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