What Is Alzheimer's Disease

The pathogenesis of Alzheimer's disease

The exact pathogenesis of AD is unclear, but it is believed to be the result of multiple factors including aging, genetics, and the environment. At present, there are many theories, of which the more widespread is the amyloid cascade hypothesis (the amyloid cascade hypothesis).

1. Amyloid Cascade Hypothesis This hypothesis holds that the deposition of Aβ in the brain is the central link of AD pathological changes, which can trigger a series of pathological processes, which further promote the deposition of Aβ, thereby forming a cascade amplification reaction. Aβ is a normal product in the brain, which is formed by the hydrolysis of amyloid precursor protein (APP) by β-secretase and γ-secretase. Aβ is mainly divided into three types: Aβ1-40, Aβ1-42, and Aβ1-43. Aβ42/43 is a β-sheet structure with strong hydrophobicity, easy deposition, and neurotoxicity. Under normal circumstances, 90% are Aβ40, with only a small amount of Aβ42/43. Due to the effect of genetic factors (such as the APP gene, presenilin 1 gene, presenilin 2 gene mutation, etc.), the ratio of Aβ42/Aβ40 in the brain of AD patients is unbalanced, and Aβ42/43 is increased. Increased Aβ42/43 deposits in the brain to form the core of senile plaques, which can activate microglia and trigger an inflammatory response; it can damage mitochondria, cause energy metabolism disorders, excessive oxygen free radicals, and lead to oxidative stress damage; can activate cells Apoptosis pathway, mediates apoptosis; it can also promote abnormal phosphorylation of tau protein by activating protein kinase; Aβ can also damage cholinergic neurons and cause lesions of the acetylcholine system. These pathological changes can promote the increase of Aβ production and abnormal deposition, resulting in a positive feedback cascade effect, which eventually leads to neuron reduction, abnormal transmitters, and clinical cognitive and behavioral symptoms. However, it is still controversial whether Aβ deposition is the initial link of AD pathogenesis. Some studies have found that amyloid plaques appear earlier than neurofibrillary tangles and neuronal loss, but other studies have found that AD pathological changes first appear in the entorhinal area. , where neurofibrillary tangles appear in the absence of Aβ deposition.

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2. Hypothesis of abnormal phosphorylation of tau protein is a microtubule-associated protein that maintains the stability of the cytoskeleton by binding to microtubules. Abnormal hyperphosphorylation of tau protein in the brain of AD patients, hyperphosphorylated tau protein aggregates to form double-stranded helical filaments, forming the main component of neurofibrillary tangles, resulting in neurotoxicity. On the other hand, due to the reduction of normal tau protein, the microtubule collapses, and the axoplasmic transport is stopped or disturbed, resulting in axonal degeneration and neuronal death. However, it is still uncertain whether tau protein phosphorylation is the initial link of AD pathological changes or secondary to abnormal Aβ.

3. Other factors and hypotheses Regarding the pathogenesis of AD, there are other hypotheses, such as genetic hypothesis, oxidative stress hypothesis, microcirculation disorder hypothesis, cholinergic hypothesis, etc., but these factors are all related to Aβ, or cause Aβ to increase, or participate in Aβ Cascade reaction, supporting the amyloid cascade hypothesis from different sides.

(1) Genetic hypothesis According to the age of onset, AD can be divided into early-onset AD (<65 years old) (early-onset Alzheimer's disease, EOAD) and late-onset AD (≥65 years old) (late-onset Alzheimer's disease, LOAD) There are two types; according to the presence or absence of family history, it can be divided into familial AD (familial Alzheimer's disease, FAD) and sporadic AD (sporadic Alzheimer's disease, SAD). FAD is mostly early-onset, accounting for about 10% of the total AD, and it is inherited in an autosomal dominant manner. Three gene mutations that can cause FAD have been found: the APP gene on chromosome 21, the presenilin 1 (PS1) gene on chromosome 14, and the presenilin 2 (PS2) gene on chromosome 1 mutation. Apolipoprotein E (ApoE) ε4 genotype (ApoEε4) is a predisposing gene for late-onset familial AD and sporadic AD. APP is hydrolyzed by β-secretase and γ-secretase to produce Aβ. PS protein may be the active center of the γ-secretase complex. APP, PS1, and PS2 gene mutations can selectively cause excessive Aβ42/43 production in brain tissue. ApoE protein is an important apolipoprotein component in plasma lipoproteins, and ApoE4 can inhibit the clearance of Aβ by astrocytes and neurons. It can be seen that genetic factors promote the pathogenesis of AD by affecting the production or clearance of Aβ.

(2) Neurotransmitter hypothesis There are various neurotransmitter abnormalities in the brain of AD patients, such as excitatory amino acids, norepinephrine, serotonin, dopamine, etc., but the cholinergic system disorder is the most serious, and it is closely related to patients. Cognitive and behavioral disorders are most closely related. Cholinergic neurons in the brain are mainly located in the nucleus of Meynert and the medial septal nucleus in the basal forebrain, projecting to the hippocampus and cerebral cortex. Studies have confirmed that cholinergic neurons in the basal forebrain of AD patients are significantly absent, choline acetyltransferase is reduced, the synthesis and release of acetylcholine are significantly reduced, and the degree of reduction is related to cognitive tests. The drugs currently used to treat AD also mainly target the acetylcholine system to improve the symptoms of patients. Therefore, the low activity of the cholinergic system may be an important link in the pathogenesis of AD.

(3) Other hypotheses include oxidative stress, immune-inflammatory mechanisms, microcirculation disorders, neurotransmitter abnormalities, etc., but their role in the pathophysiological process of AD is still unclear, and most of them are related to the abnormal deposition of Aβ, which may be Both belong to the category of the amyloid cascade hypothesis.

The pathological changes of Alzheimer's disease

The general pathology of AD patients is mainly brain atrophy; the main pathological changes such as neuritic plaques, neurofibrillary tangles, neuron reduction, and cerebral amyloid angiopathy can be seen under the microscope.

1. The gross pathology is mainly brain atrophy, with narrowed gyri, widened sulci, and enlarged ventricles. Brain atrophy begins in the entorhinal cortex and gradually extends to the hippocampus, intertemporal lobe, and frontoparietal regions as the disease progresses, while the primary sensory and motor cortex (occipital visual cortex, precentral gyrus, and postcentral gyrus) are relatively preserved.

2. Microscopic pathology Microscopic pathological changes are mainly neuritic plaques, neurofibrillary tangles, neuronal reduction, amyloid vascular degeneration, in addition, hippocampal neuronal granular vacuolar degeneration, gliosis, neuropil filaments can also be seen Wait.

(1) Neuritic plaques, also known as senile plaques (SP), are one of the main lesions of AD. Located outside the cell, its core component is Aβ containing 40-43 amino acids, surrounded by a crown composed of degenerated axons, dendrites, amyloid fibers, glial cell protrusions, and microglia. SP can be divided into three stages: primitive or early plaques, classic or mature plaques, and burnout or dense plaques, which may be related to the development of AD from early to late stages. The distribution of SP in the brain is not uniform, and there are large differences between individuals, but generally, the hippocampus, temporal lobe, and frontal lobe are concentrated areas.

Protein plaques and neurofibrillary tangles pattern map Protein plaques and neurofibrillary tangles pattern map image translated from the website of the United States Health Aid Foundation (2) Neurofibrillary tangles (neurofibrillary tangles, NFTs) is another major pathological change in AD, Located in the cytoplasm of neurons, its main component is aberrantly phosphorylated microtubule-associated tau protein. Under normal circumstances, tau protein binds to microtubules and maintains the stability of the cytoskeleton. In AD brain, tau protein is abnormally phosphorylated, and the binding point to microtubules is reduced. The abnormally phosphorylated tau protein binds to itself to form double-helical filaments. , eventually leading to the formation of NFTs. The distribution of NFTs in the brain has a certain pattern, the hippocampus is the most, followed by the amygdala and temporal lobe, and can be extended to the frontal lobe and the temporoparietal junction in the late stage. Its distribution and density correlate with the degree of dementia.

(3) Various pathological processes eventually lead to the loss of neurons in the AD brain, especially the loss of cholinergic neurons in the hippocampus and basal forebrain, and the loss of neurons can reach 47%. As the disease progresses, there is also severe neuronal loss in the temporal and frontal cortex, with less involvement in the primary sensory and motor cortex.

(4) Amyloid cerebrovascular disease is common in AD patients, and the incidence is close to 90%. The amyloid in blood vessels in the same protein as Aβ in neuritic plaques and other deposits. The diseased blood vessels are mainly located in the pia mater and cerebral cortex. . Amyloid angiopathy in AD patients is different from pure amyloidotic cerebrovascular disease, which is an independent disease without the pathological changes of AD.

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