AD发生了什么

 

neuron的功能和生存依赖于几个重要的biological process：

1. Communication

神经元不断地与相邻的脑细胞进行touch。

神经递质分子有特异性。每个神经递质分子bind to附近神经元的树突上特异的受体位点。

科学家估计，一个神经元与其它的神经元有7000个突触连接。

2.Metabolism（the breaking down of chemicals and nutrients within a cell）

细胞需要脑内的血液循环系统提供oxygen和glucose作为能量。

大脑是供血最丰富的器官之一。消耗身体20%的能量，比其他器官多。

cells require energy in the form of oxygen and glucose, which are supplied by blood circulating through the brain. 

The brain has one of the richest blood supplies of any organ and consumes up to 20 percent of the energy used by the human body—more than any other organ.

3.Repair, remodeling, and regeneration.

与身体内的大多数细胞不同，神经元是永生的，在人体内可存活100年。成人的大脑可能产生新的神经元（称作：神经发生）。突触连接的重塑和神经发生对学习、记忆和大脑修复很重要。

Adult brains may even generate new neurons—a process called neurogenesis. Remodeling of synaptic connections and neurogenesis are important for learning, memory, and possibly brain repair.

glial cells

glial cells胶质细胞是脑内数量最多的细胞，与神经元的比例是10:1。包括：microglia, astrocytes, and oligodendrocytes。它们包绕这神经元，并给神经元提供功能支持。

For example, microglia protect neurons from physical and chemical damage and are responsible for clearing foreign substances and cellular debris(残骸) from the brain. To carry out these functions, glial cells often collaborate with blood vessels in the brain. Together, glial and blood vessel cells regulate the delicate balance within the brain to ensure that it functions at its best.

How Does Alzheimer’s Disease Affect the Brain?

健康人的大脑在衰老过程中，会萎缩，但神经元不会大量丢失。但是，AD的大脑中：many neurons stop functioning, lose connections with other neurons, and die。

阿尔茨海默氏症扰乱了对神经元及其神经元网络很重要的过程，包括通讯、新陈代谢和修复。

AD最开始影响的是内嗅皮层和海马；然后，影响负责语言、推理和社交的脑皮层；最后，很多其它脑区也受到影响。

At first, Alzheimer’s disease typically destroys neurons and their connections in parts of the brain involved in memory, including the entorhinal cortex and hippocampus. It later affects areas in the cerebral cortex responsible for language, reasoning, and social behavior. Eventually, many other areas of the brain are damaged.

What Are the Main Characteristics of the Brain with Alzheimer’s?

1. Amyloid Plaques

Beta-amyloid protein is formed from the breakdown of a larger protein, called amyloid precursor protein.

Beta-amyloid 42是其中的一种形式，它是toxic. AD的大脑中，tau蛋白clump together to form plaqu，disrupt cell function.

研究者研究在疾病的哪个阶段，各种形式的beta-amyloid是如何影响AD的。

2.Neurofibrillary Tangles

神经纤维缠结是神经元内部tau蛋白的异常累积。正常神经元的内部被一种称为微管的结构所支撑，这种微管能够guide营养和分子从胞体到树突/轴突。tau蛋白附着在微管上，并支撑微管。

但是，在AD中，abnormal chemical changes导致tau蛋白从微管上脱离，并附着在其它tau分子上成线状，最终聚在一起形成缠结。

这些缠结阻断了神经元的运输系统，对神经元之间的突触传递有害。

Neurofibrillary tangles are abnormal accumulations of a protein called tau that collect inside neurons.

Healthy neurons, in part, are supported internally by structures called microtubules, which help guide nutrients and molecules from the cell body to the axon and dendrites. In healthy neurons, tau normally binds to and stabilizes microtubules. In Alzheimer’s disease, however, abnormal chemical changes cause tau to detach from microtubules and stick to other tau molecules, forming threads that eventually join to form tangles inside neurons. These tangles block the neuron’s transport system, which harms the synaptic communication between neurons.

Emerging evidence suggests that Alzheimer’s-related brain changes may result from a complex interplay among abnormal tau and beta-amyloid proteins and several other factors. It appears that abnormal tau accumulates in specific brain regions involved in memory. Beta-amyloid clumps into plaques between neurons. As the level of beta-amyloid reaches a tipping point, there is a rapid spread of tau throughout the brain.

Chronic Inflammation

研究者认为chronic inflammation是由于glial cell的累积导致的。glial cell负责清除大脑内的残骸的。

microglia engulfs and destroys waste and toxins in healthy brain。在AD中，microglia fail to clear away waste, debris, and protein collections, including beta-amyloid plaques.

研究者正试图找出为什么AD中microglia失去了这一功能。

这方面的一个重点研究是TREM2。正常情况下，TREM2告诉microglial cell清除beta-amyloid paques、对抗炎症。如果这个基因异常，神经元之间形成斑块。astrocyte cell帮助清除剩余的斑块和细胞残骸。

microglial和astrocyte聚集在神经元周围，但是无法执行清除功能。它们释放化学物质导致炎症，对它们本要保护的神经元造成损伤。

Vascular Contributions to Alzheimer’s Disease

任何血管的问题，比如：beta-amyloid在脑血管的沉积、动脉粥样硬化、mini-stroke可能也参与了AD的病变。

vascular problem减少大脑的血流量和氧气，并损害了大脑屏障。在一个AD患者中，受损的血脑屏障阻止glucose进入大脑，以及beta-amyloid和tau蛋白的清除。这导致炎症，加重了大脑的血管问题。

vascular problem好像是AD的原因和结果，研究者正试图干扰这个既复杂又有害的循环。

Loss of Neuronal Connections and Cell Death

在AD中存在遍及大脑的神经元损伤和死亡，所以神经元之间的网络也受损，一些脑区开始缩小。在AD的最后阶段，这个过程（被称为大脑萎缩）广泛存在，导致脑体积的显著减少。

自己：神经元丢失发生在不同的脑区。不同区域的神经元丢失差别很大，海马椎体细胞层可达60%，基底核、额颞叶新皮层某些区域可大于80%。 

 

参考文献：https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease

附原文：

What Happens to the Brain in Alzheimer's Disease?

The healthy human brain contains tens of billions of neurons—specialized cells that process and transmit information via electrical and chemical signals. They send messages between different parts of the brain, and from the brain to the muscles and organs of the body. Alzheimer’s disease disrupts this communication among neurons, resulting in loss of function and cell death.

Key Biological Processes in the Brain

Most neurons have three basic parts: a cell body, multiple dendrites, and an axon.

• The cell body contains the nucleus, which houses the genetic blueprint that directs and regulates the cell’s activities.
• Dendrites are branch-like structures that extend from the cell body and collect information from other neurons.
• The axon is a cable-like structure at the end of the cell body opposite the dendrites and transmits messages to other neurons.

The function and survival of neurons depend on several key biological processes:

• Communication. Neurons are constantly in touch with neighboring brain cells. When a neuron receives signals from other neurons, it generates an electrical charge that travels down the length of its axon and releases neurotransmitter chemicals across a tiny gap, called a synapse. Like a key fitting into a lock, each neurotransmitter molecule then binds to specific receptor sites on a dendrite of a nearby neuron. This process triggers chemical or electrical signals that either stimulate or inhibit activity in the neuron receiving the signal. Communication often occurs across networks of brain cells. In fact, scientists estimate that in the brain’s communications network, one neuron may have as many as 7,000 synaptic connections with other neurons.
• Metabolism. Metabolism—the breaking down of chemicals and nutrients within a cell—is critical to healthy cell function and survival. To perform this function, cells require energy in the form of oxygen and glucose, which are supplied by blood circulating through the brain. The brain has one of the richest blood supplies of any organ and consumes up to 20 percent of the energy used by the human body—more than any other organ.
• Repair, remodeling, and regeneration. Unlike many cells in the body, which are relatively short-lived, neurons have evolved to live a long time—more than 100 years in humans. As a result, neurons must constantly maintain and repair themselves. Neurons also continuously adjust, or “remodel,” their synaptic connections depending on how much stimulation they receive from other neurons. For example, they may strengthen or weaken synaptic connections, or even break down connections with one group of neurons and build new connections with a different group. Adult brains may even generate new neurons—a process called neurogenesis. Remodeling of synaptic connections and neurogenesis are important for learning, memory, and possibly brain repair.

Neurons are a major player in the central nervous system, but other cell types are also key to healthy brain function. In fact, glial cells are by far the most numerous cells in the brain, outnumbering neurons by about 10 to 1. These cells, which come in various forms—such as microglia, astrocytes, and oligodendrocytes—surround and support the function and healthy of neurons. For example, microglia protect neurons from physical and chemical damage and are responsible for clearing foreign substances and cellular debris from the brain. To carry out these functions, glial cells often collaborate with blood vessels in the brain. Together, glial and blood vessel cells regulate the delicate balance within the brain to ensure that it functions at its best.

How Does Alzheimer’s Disease Affect the Brain?

The brain typically shrinks to some degree in healthy aging but, surprisingly, does not lose neurons in large numbers. In Alzheimer’s disease, however, damage is widespread, as many neurons stop functioning, lose connections with other neurons, and die. Alzheimer’s disrupts processes vital to neurons and their networks, including communication, metabolism, and repair.

At first, Alzheimer’s disease typically destroys neurons and their connections in parts of the brain involved in memory, including the entorhinal cortex and hippocampus. It later affects areas in the cerebral cortex responsible for language, reasoning, and social behavior. Eventually, many other areas of the brain are damaged. Over time, a person with Alzheimer’s gradually loses his or her ability to live and function independently. Ultimately, the disease is fatal.