Introduction
As the most widely recognized neurodegenerative disease, there has been no effective treatment for Alzheimer's disease. On June 3, an article published on Nature Neuroscience revealed that the cause of alzheimer's disease (AD) is the lysosomal acidification disorder, which is the most likely to be close to the truth. However, this is not a small distance from the final development of drugs for Alzheimer's disease.
The characteristics of neuropathological changes in AD brain include, a β Amyloid plaques formed by protein deposition, neurofibrillary tangles (intracellular aggregates composed of hyperphosphorylated tau proteins), synaptic loss and atrophy, selective depletion of neurotransmitter systems (such as acetylcholine) and Lewy bodies (a few cases), which lead to the disorder of information exchange between neurons and even the death of neurons, and finally lead to ad. Therefore, the current thinking of drug development mainly focuses on clearance β Amyloid protein (a β Protein), regulating tau protein, and ache (acetylcholinesterase inhibitor), but in recent years, there are also some new mechanisms and treatments of AD, such as inflammation theory, stem cell therapy and gene therapy. Alzheimer's disease neuropathology includes numerous amyloid proteins- β (A β) Extracellular amyloid plaques of oligomers and intraneuronal tangles containing phosphorylated tau. Microglia and astrocytes are activated, leading to the spread of neuroinflammation and neuropathology. A β Protein cascade hypothesis a β Protein is the main protein component of diffuse and neuroinflammatory plaques, which originates from the proteolysis of amyloid precursor protein (APP). App is a type 1 integrated transmembrane protein with a β The C-terminal part of is embedded in the cell membrane. Generate a β Protein requires two consecutive protein hydrolysis steps, which are firstly determined by β- Secretory enzyme in a β The N-terminal region of the sequence cleaves app, producing slightly shorter soluble N-terminals (apps β） And amyloid C-terminal fragment (C99), β- The cleavage of C99 by secretase releases 50 residues at the C-terminal of app, called app intracellular domain (AICD) and a β。
In the process of its decomposition, lysosomes in cells take on most of the work. Lysosomal acidification disorders lead to cellular errors in the production of a β The protein can't be decomposed normally, and then support the lysosome, making the cell rupture and a β The protein is released outside the cell and further forms plaque.
A β Proteins can trigger a series of signal cascades. Studies have found that they can reduce synaptic plasticity (characteristics of adjustable synaptic connection strength (neurotransmitter release, sensitive type of cell receiving synapse, etc.) or reduce synaptic density through the following ways. 1. It binds to cellular prion protein (PrPC), activates Fyn kinase, and then turns on long-term inhibition of synapses (LTD) through NMDA type glutamate receptor (NMDAR) pathway. 2. The non NMDAR pathway forms a ternary complex with PrPc and metabotropic glutamate 5 receptors (mglu5rs), resulting in impaired synaptic plasticity and decreased synaptic density. 3. A β The accumulation of tau protein can indirectly lead to the accumulation and diffusion of tau protein in brain regions. 4、A β Protein can inhibit acetylcholine receptor (AChR), induce Ltd, and lead to inhibition of synaptic transmission. Current situation of drug research and development using monoclonal antibodies to bind extracellular a β Protein monomer / soluble aggregate (the most mainstream method at present) to prevent its polymerization or stimulate downstream signal pathways. The representative drugs are aducanumab of Baijian, donanemab of Lilly and crenezumab of Roche. But according to a β Signal cascade theory, in a β The production of protein and the process of degradation have opportunities for drug research and development. At present, some drug research and development is aimed at app to produce a β Protein process β- Secretase and develop its inhibitor (beta secretase inhibitor/bace), such as mh-84 of Frankfurt University and mbi-10 of MSD. However, these are currently in the pre clinical research stage, and there is still a long way to go before becoming a patent medicine. There are also other research directions, such as a β Aggregation inhibitor (trimeric acid, sharinositol, pbt2) a β Antigen (AN-1792, vanutide, ad02, cad-106) anti-A β Polyclonal antibody (immunoglobulin) γ- Secretase inhibitors (begacestat, semagacestat and avagacestat) γ- Secretory enzyme regulator (tarenflurbil) β- Site amyloid precursor protein lyase (bace) inhibitors (ly2811376, ly2886721, azd3839, verubecestat, atabecestat, and lanabecestat). Blocking its downstream pathway can also be used as a new idea for AD drug development. For example, an article published on science on June 1 this year revealed that mglu5rs' silent (SAM) allosteric modulator (bms-984923, Bristol Myers Squibb) can reverse synaptic loss in Alzheimer's mice. There are also NMDA drugs developed for the NMDAR pathway. Although this drug has a good effect on improving neurocognition, it is easy to cause depression. Tau protein hypothesis tau is one of the microtubule associated proteins (map) that stabilize neuronal microtubules, mainly in axons (compared with somatic dendritic MAP2). The information transmission between neurons depends on microtubules as the orbit, and tau protein combines with microtubules to maintain its stability. When the key site of tau is phosphorylated (mainly ser262 or ser214), tau is released from the bound microtubules, resulting in microtubule rupture and tau aggregation into paired helices (PHF). Tau hyperphosphorylation and neurofibrillary tangles are key components of AD pathology and are believed to be caused by upstream a of the human brain β Synaptic pathology driven, and with a β Synergism to further synaptic loss.
The key phosphorylation site tau contains an acidic N-terminal domain, a basic and proline rich intermediate domain, a basic domain containing three or four internal repeats, and a C-terminal domain. It can be phosphorylated at multiple sites, some of which regulate its microtubule binding properties. Several ser pro or thr Pro motifs that appear in two regions on both sides of the internal repeat sequence have only a moderate effect on tau microtubule interaction, but can be used as a diagnostic tool for ad like tau phosphorylation. It is also a target of proline directed kinases, such as glycogen synthase kinase 3, cyclin dependent kinase Cdk5 or MAP kinase. Other sites include protein kinase A (such as ser214), microtubule affinity regulated kinase (mark, at kxgs motif, including ser262, ser356), or targets of Ca 2+ / calmodulin dependent protein kinase (ser416). Research and development ideas of tau protein
Many abnormal phosphorylation sites are located on ser pro or thr Pro motifs, so various antibodies developed for ad tau react with these phosphorylation sites. Recently, genome-wide association studies have shown that the accumulation of neuroinflammation is a genetic risk factor that mediates the onset and progression of AD. In human studies, more than 25 genetic loci are associated with the risk of AD, most of which are mainly expressed in microglia and related to neuroinflammation. Neuroinflammation can promote a β Protein production and induced tau phosphorylation. Neuroinflammation and its downstream pathway a β Microglia around the plaque are activated to a pro-inflammatory state and secrete interleukin (IL) -1 β。 IL-1 β Promote soluble amyloid precursor protein (Sapp) in neurons α Generation of, Sapp α By activating nuclear factor kappa B (NF- κ B) Pro-il-1 in signal transduction microglia β Generation of. At the same time, a β Activate NLRP3 inflammatory body, produce activated caspase-1 from inactivated procaspase-1, and cause microglia to further secrete IL-1 β。 This cycle makes neuroinflammatory events chronic and induces hyperphosphorylation of tau and reduction of synaptic proteins in neurons by activating p38 mitogen activated protein kinase (p38 MAPK) pathway. The representative pro-inflammatory factors regulating neuroinflammation of microglia in Alzheimer's disease (AD) hypothesized by neuropathology research are the regulatory factors related to the neuroinflammatory mechanism of AD, including bone marrow cell-2 (TREM2) transmembrane protein (the reduction of its hydrolytic cleavage will aggravate neuroinflammation and is a regulator of brain microglia activity), leucine repeat sequence (NLR) rich in nucleotide binding domain and pyrin domain 3 (NLRP3), Apoptosis related dot like protein (ASC), CD33 and CD22 containing caspase recruitment domain (ASC). Calcium homeostasis regulator in the brain, microglia is the most abundant type of immune cells, accounting for more than 80% of all immune cells. Calcium homeostasis is closely related to microglia activation, a β Increase intracellular calcium levels, which in turn contributes to the activation of NLRP3 inflammatory bodies in microglia. The role of calcium homeostasis regulator family proteins (calhm, CALHM1, calhm2 and calhm3) has attracted more and more attention in the field of AD research. In calhm2 knockout mice, a β Sedimentation and neuroinflammation were significantly reduced, and ad related cognitive impairment was alleviated. Gene therapy apoE4 currently has identified that the gene related to ad is ApoE gene mutation, especially apoE4 gene. The role of this gene can be referred to as a breakthrough! Cell published an article on the mechanism of apoE4 causing Alzheimer's disease. At present, there are also some clinical trials aimed at this gene. Peroxisome proliferator activated receptor γ Coactivator-1 α （PGC-1 α） PGC-1 α Mainly involved in regulation β- Production of APP cleaving enzyme 1 (BACE-1), which is responsible for a β Production of. One involves exposure to hpgc-1 α The clinical trials of APP23 transgenic mice showed that the memory of mice was improved and amyloid deposits were reduced. In addition, due to the increased expression of NGF and brain-derived neurotrophic factor, crispr/cas9ad also has a neuroprotective effect. Crispr/cas9ad has the genetic basis of susceptibility to app, PSEN1 and psen2 gene mutations. It is also related to the expression of apoE4 alleles. These gene loci can be used as therapeutic targets. At present, there have been some targeted treatment studies using CRISPR, as follows:
Summary
More and more evidence shows that ad is a heterogeneous disease caused by various pathophysiological mechanisms beyond typical dogma. For example, up to one-third of patients clinically diagnosed with ad do not have a β Accumulation, and many patients diagnosed with ad in postmortem biopsy did not show cognitive impairment. Current theories believe that Alzheimer's disease may have different causes of disease like cancer, so identifying molecular biomarkers of ad to distinguish different subtypes may be the key to develop more effective drugs, and in the future, drugs for the treatment of Alzheimer's disease with differentiated causes will bloom.
