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90-418: 1CZZ , 1D00 , 1FLL , 1LB6 , 3QD6 , 5DMJ , 5IHL , 5DMI 958 21939 ENSG00000101017 ENSMUSG00000017652 P25942 P27512 NM_001362758 NM_011611 NM_170702 NM_170703 NM_170704 NP_001349687 NP_035741 NP_733803 NP_733804 NP_733805 Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and

180-520: A T cell surface molecule which is capable of induction of contact dependent differentiation of B cells. The protein receptor encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. AT-hook transcription factor AKNA

270-410: A chemokine receptor on the surface of a T helper cell to gain entry. The number of CD4 and CD8 T cells in blood is often used to monitor the progression of HIV infection . While CD molecules are very useful in defining leukocytes, they are not merely markers on the cell surface . Though only a fraction of known CD molecules have been thoroughly characterised, most of them have important functions. In

360-406: A proteolytic process which causes APP to be divided into smaller fragments. Although commonly researched as neuronal proteins, APP and its processing enzymes are abundantly expressed by other brain cells. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as amyloid plaques. Excitatory neurons are known to be

450-575: A stem cell , as opposed to a fully differentiated endothelial cell . Some cell populations can also be defined as , , or (alternatively, , , or ), indicating an overall variability in CD expression , particularly when compared to other cells being studied. A review of the development of T cells in the thymus uses this nomenclature to identify cells transitioning from CD4 /CD8 double-positive cells to CD4 /CD8 . Since 1982 there have been nine Human Leukocyte Differentiation Antigen Workshops culminating in

540-426: A conference. The CD system is commonly used as cell markers in immunophenotyping , allowing cells to be defined based on what molecules are present on their surface. These markers are often used to associate cells with certain immune functions . While using one CD molecule to define populations is uncommon (though a few examples exist), combining markers has allowed for cell types with very specific definitions within

630-470: A consequence of aging, the brains of people with Alzheimer's disease have a greater number of them in specific brain regions such as the temporal lobe . Lewy bodies are not rare in the brains of people with Alzheimer's disease. Alzheimer's disease has been identified as a protein misfolding disease , a proteopathy , caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in

720-456: A decline from a prior level of function and the diagnosis requires ruling out other common causes of neurocognitive decline. Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single-photon emission computed tomography (SPECT) or positron emission tomography (PET), can be used to help exclude other cerebral pathology or subtypes of dementia. On MRI or CT, Alzheimer's disease usually shows

810-404: A generalized or focal cortical atrophy, which may be asymmetric. Atrophy of the hippocampus is also commonly seen. Brain imaging commonly also shows cerebrovascular disease, most commonly previous strokes (small or large territory strokes), and this is thought to be a contributing cause of many cases of dementia (up to 46% cases of dementia also have cerebrovascular disease on imaging). FDG-PET scan

900-409: A large scale study conducted on 6,245,282 patients has shown an increased risk of developing Alzheimer's disease following COVID-19 infection in cognitively normal individuals over 65. Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in

990-435: A mechanism of cell death in brain cells affected with tau tangles. Exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of Alzheimer's disease is not known. The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils , which are believed to be

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1080-447: A person's condition declines, they often withdraw from family and society . Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to twelve years. The cause of Alzheimer's disease is poorly understood. There are many environmental and genetic risk factors associated with its development. The strongest genetic risk factor

1170-501: A result of this net stimulation, the B cell can undergo division, antibody isotype switching , and differentiation to plasma cells . The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target. Early evidence for these effects were that in CD40 or CD40L deficient mice, there is little class switching or germinal centre formation, and immune responses are severely inhibited. The expression of CD40

1260-464: A result, individuals with hyper-IgM syndrome are susceptible to a wide range of infections and have an increased risk of autoimmune diseases and cancer. Currently, treatment for hyper-IgM syndrome involves the replacement of missing immunoglobulins, as well as other therapies to boost the immune system and prevent infections. Research is ongoing to better understand the role of CD40 in hyper-IgM syndrome and to develop new treatments for this disorder. CD40

1350-532: A role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in Alzheimer's disease or a marker of an immunological response . There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression. Alterations in

1440-561: Is APOEε4 . APOEε4 is one of four alleles of apolipoprotein E (APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and the ε4 allele disrupts this function. Between 40% and 80% of people with Alzheimer's disease possess at least one APOEε4 allele. The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes . Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance . For example, Nigerian Yoruba people do not show

1530-421: Is a neurodegenerative disease that usually starts slowly and progressively worsens, and is the cause of 60–70% of cases of dementia . The most common early symptom is difficulty in remembering recent events . As the disease advances, symptoms can include problems with language , disorientation (including easily getting lost), mood swings , loss of motivation , self-neglect , and behavioral issues . As

1620-488: Is a medical hypothesis that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination , the brains of people with Alzheimer's disease go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter. Likewise the hypothesis is, that as infants go through states of cognitive development , people with Alzheimer's disease go through

1710-569: Is a primary immunodeficiency disorder characterized by increased serum levels of immunoglobulin (Ig) M and decreased levels of IgG, IgA, and IgE. CD40 is involved in the development of hyper-IgM syndrome in that it serves as a co-stimulatory molecule in the activation differentiation of B cells, which play a key role in producing immunoglobulins. In hyper-IgM syndrome, mutations in genes involved in CD40 signaling result in impaired B cell activation and differentiation, leading to increased production of IgM and decreased production of other immunoglobulins. As

1800-418: Is a promising target for the development of drugs to treat a variety of diseases, including cancer, autoimmune diseases, and chronic inflammation. By targeting CD40, it is possible to modulate the immune response and enhance the ability of the body to fight against diseases. For example, drugs that block CD40 signaling have shown promise in treating autoimmune diseases, such as rheumatoid arthritis, by suppressing

1890-493: Is about 90% heritable. Familial Alzheimer's disease usually implies two or more persons affected in one or more generations. Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encoding amyloid-beta precursor protein (APP) and presenilins PSEN1 and PSEN2 . Most mutations in the APP and presenilin genes increase the production of a small protein called amyloid beta (Aβ)42, which

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1980-441: Is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD40L interactions may play a role in the control of B cell haematopoiesis . CD40 (protein) has been shown to interact with TRAF2 , TRAF3 , TRAF6 , TRAF5 and TTRAP . The remaining member of TRAF4 family, namely TRAF4 , positively regulates CD40 signalling, but interacts with CD40 indirectly. CD40 also interacts with CD40L, due to

2070-515: Is available and can be examined histologically for senile plaques and neurofibrillary tangles. There are three sets of criteria for the clinical diagnoses of the spectrum of Alzheimer's disease: the 2013 fifth edition of the Diagnostic and Statistical Manual of Mental Disorders ( DSM-5 ); the National Institute on Aging - Alzheimer's Association (NIA-AA) definition as revised in 2011; and

2160-491: Is believed to occur when abnormal amounts of amyloid beta (Aβ), accumulating extracellularly as amyloid plaques and tau proteins , or intracellularly as neurofibrillary tangles , form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. This altered protein clearance ability is age-related, regulated by brain cholesterol, and associated with other neurodegenerative diseases. The cause for most Alzheimer's cases

2250-435: Is complex and focuses on asymptomatic individuals; the latter two stages describe individuals experiencing symptoms. The core clinical criteria for MCI is used along with identification of biomarkers, predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition. The core clinical criteria itself rests on the presence of cognitive impairment without the presence of comorbidities. The third stage

2340-405: Is disrupted in Alzheimer's disease, though it remains unclear whether this is produced by or causes the changes in proteins. Smoking is a significant Alzheimer's disease risk factor. Systemic markers of the innate immune system are risk factors for late-onset Alzheimer's disease. Exposure to air pollution may be a contributing factor to the development of Alzheimer's disease. Retrogenesis

2430-493: Is diverse. CD40 is constitutively expressed by antigen presenting cells, including dendritic cells , B cells and macrophages . It can also be expressed by endothelial cells , smooth muscle cells , fibroblasts and epithelial cells. Consistent with its widespread expression on normal cells, CD40 is also expressed on a wide range of tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, myeloma and some carcinomas including nasopharynx, bladder, cervix, kidney and ovary. CD40

2520-514: Is divided into probable and possible AD dementia. In probable AD dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction. In possible AD dementia, another causal disease such as cerebrovascular disease is present. Neuropsychological tests including cognitive tests such as the mini–mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA) and

2610-547: Is frequently seen as a prodromal stage of Alzheimer's disease. Amnesic MCI has a greater than 90% likelihood of being associated with Alzheimer's. In people with Alzheimer's disease, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception ( agnosia ), or execution of movements ( apraxia ) are more prominent than memory problems. Alzheimer's disease does not affect all memory capacities equally. Older memories of

2700-513: Is from an allele of apolipoprotein E . Other risk factors include a history of head injury , clinical depression , and high blood pressure . The progression of the disease is largely characterized by the accumulation of malformed protein deposits in the cerebral cortex , called amyloid plaques and neurofibrillary tangles . These misfolded protein aggregates interfere with normal cell function, and over time lead to irreversible degeneration of neurons and loss of synaptic connections in

2790-406: Is known to target the hippocampus which is associated with memory , and this is responsible for the first symptoms of memory impairment. As the disease progresses so does the degree of memory impairment. The first symptoms are often mistakenly attributed to aging or stress . Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills

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2880-453: Is named after German psychiatrist and pathologist Alois Alzheimer , who first described it in 1906. Alzheimer's financial burden on society is large, with an estimated global annual cost of US$ 1   trillion. It is ranked as the seventh leading cause of death worldwide. Given the widespread impacts of Alzheimer's disease, both basic-science and health funders in many countries support Alzheimer's research at large scales. For example,

2970-558: Is not required for the diagnosis but it is sometimes used when standard testing is unclear. FDG-PET shows a bilateral, asymetric, temporal and parietal reduced activity. Advanced imaging may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease. FDA-approved radiopharmaceutical diagnostic agents used in PET for Alzheimer's disease are florbetapir (2012), flutemetamol (2013), florbetaben (2014), and flortaucipir (2020). Because many insurance companies in

3060-505: Is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta -induced microglial activation , and thus is thought to be an early event in Alzheimer disease pathogenesis. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. In

3150-509: Is required for their activation. The binding of CD154 ( CD40L ) on T H cells to CD40 activates antigen presenting cells and induces a variety of downstream effects. Activated CD4+ T cells primarily exhibit its ligand CD40L/CD154 to antigen-presenting cells including dendritic cells (DCs), B cells, macrophages, classical and non-classical monocytes, on a variety of non-immune cells including platelets and endothelial cells, and on several types of tumor cells. Mutations affecting this gene are

3240-427: Is still mostly unknown, except for 1–2% of cases where deterministic genetic differences have been identified. Several competing hypotheses attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis. The oldest hypothesis, on which most drug therapies are based, is the cholinergic hypothesis , which proposes that Alzheimer's disease is caused by reduced synthesis of

3330-510: Is the Aβ oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all the usual pathologies of Alzheimer's disease. The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments . Eventually, they form neurofibrillary tangles inside neurons. When this occurs,

3420-518: Is the main component of amyloid plaques . Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain. Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1 . Alleles in the TREM2 gene have been associated with a three to five times higher risk of developing Alzheimer's disease. A Japanese pedigree of familial Alzheimer's disease

3510-536: Is usually clinically diagnosed based on a person's medical history , observations from friends or relatives, and behavioral changes. The presence of characteristic neuropsychological changes with impairments in at least two cognitive domains that are severe enough to affect a person's functional abilities are required for the diagnosis. Domains that may be impaired include memory (most commonly impaired), language, executive function , visuospatial functioning, or other areas of cognition. The neurocognitive changes must be

3600-570: The brain . A probable diagnosis is based on the history of the illness and cognitive testing , with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal brain aging . Examination of brain tissue is needed for a definite diagnosis, but this can only take place after death . No treatments can stop or reverse its progression, though some may temporarily improve symptoms. A healthy diet, physical activity, and social engagement are generally beneficial in aging, and may help in reducing

3690-428: The differential diagnosis of Alzheimer's disease and other diseases. Interviews with family members are used in assessment; caregivers can supply important information on daily living abilities and on the decrease in the person's mental function . A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonly unaware of their deficits . Many times, families have difficulties in

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3780-468: The hippocampus . However, Alzheimer's disease may occur without neurofibrillary tangles in the neocortex . Plaques are dense, mostly insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons . Neurofibrillary tangles are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as

3870-420: The macrophage , the primary signal for activation is IFN-γ from T h 1 type CD4 T cells . The secondary signal is CD40L (CD154) on the T h 1 cell which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface which helps increase the level of activation. The increase in activation results in the induction of potent microbicidal substances in

3960-610: The microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. A number of studies connect the misfolded amyloid beta and tau proteins associated with the pathology of Alzheimer's disease, as bringing about oxidative stress that leads to neuroinflammation . This chronic inflammation is also a feature of other neurodegenerative diseases including Parkinson's disease , and ALS . Spirochete infections have also been linked to dementia. DNA damages accumulate in Alzheimer's diseased brains; reactive oxygen species may be

4050-619: The temporal lobe and parietal lobe , and parts of the frontal cortex and cingulate gyrus . Degeneration is also present in brainstem nuclei particularly the locus coeruleus in the pons . Studies using MRI and PET have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults. Both Aβ plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those with Alzheimer's disease, especially in

4140-591: The CD40/CD40LG axis is important for immune cell turnover and homeostasis under normal conditions. This is hypothesized because the closest association of cell proliferation is with CD40LG and the pro-apoptotic marker BAX also this axis plays a crucial role in promoting B cell activation and proliferation, the B-T cell immune synapses among with antigen presentation The CD40 molecule is a potential target for cancer immunotherapy . Anti-CD40 monoclonal antibodies may help promote

4230-600: The International Working Group criteria as revised in 2010. Three broad time periods, which can span decades, define the progression of Alzheimer's disease from the preclinical phase, to mild cognitive impairment (MCI), followed by Alzheimer's disease dementia. Eight intellectual domains are most commonly impaired in AD— memory , language , perceptual skills , attention , motor skills , orientation , problem solving and executive functional abilities, as listed in

4320-513: The Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD. These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems; more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. Further neurological examinations are crucial in

4410-727: The US National Institutes of Health program for Alzheimer's research, the National Plan to Address Alzheimer’s Disease, has a budget of US$ 3.98 billion for fiscal year 2026. In the European Union , the 2020 Horizon Europe research programme awarded over €570 million for dementia-related projects. The course of Alzheimer's is generally described in three stages, with a progressive pattern of cognitive and functional impairment . The three stages are described as early or mild, middle or moderate, and late or severe. The disease

4500-526: The United States do not cover this procedure, its use in clinical practice is largely limited to clinical trials as of 2018 . Assessment of intellectual functioning including memory testing can further characterise the state of the disease. Medical organizations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. Definitive diagnosis can only be confirmed with post-mortem evaluations when brain material

4590-437: The brain. Late-onset Alzheimer's is about 70% heritable . Genetic models in 2020 predict Alzheimer's disease with 90% accuracy. Most cases of Alzheimer's are not familial , and so they are termed sporadic Alzheimer's disease. Of the cases of sporadic Alzheimer's disease, most are classified as late onset where they are developed after the age of 65 years. The strongest genetic risk factor for sporadic Alzheimer's disease

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4680-404: The brain. Plaques are made up of small peptides , 39–43  amino acids in length, called amyloid beta. Amyloid beta is a fragment from the larger amyloid-beta precursor protein (APP) a transmembrane protein that penetrates the cell's membrane . APP is critical to neuron growth, survival, and post-injury repair. In Alzheimer's disease, gamma secretase and beta secretase act together in

4770-420: The cause of autosomal recessive hyper-IgM immunodeficiency. Between the late 1950s and the mid-1980s, several immunology laboratories started to use the new hybridoma technology to develop monoclonal antibodies (mAbs) and define receptors expressed at different stages of hematopoietic cell differentiation. The goal of these experiments was to identify differentiation antigens that could be used to describe

4860-523: The cell to the ends of the axon and back. A protein called tau stabilises the microtubules when phosphorylated , and is therefore called a microtubule-associated protein . In Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. Pathogenic tau can also cause neuronal death through transposable element dysregulation. Necroptosis has also been reported as

4950-539: The clinical criteria for diagnosis of Alzheimer's disease. These early symptoms can affect the most complex activities of daily living . The most noticeable deficit is short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information. Subtle problems with the executive functions of attentiveness , planning , flexibility, and abstract thinking , or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of

5040-478: The demyelinating disease, multiple sclerosis , and Alzheimer's disease have been reported. The association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with celiac disease while a 2018 review found an association with several types of dementia including Alzheimer's disease. Studies have shown a potential link between infection with certain viruses and developing Alzheimer's disease later in life. Notably,

5130-426: The designation (e.g., CD2 molecule). Currently, "CD2" is generally used to designate the molecule, and "CD2 antibody " is used to designate the antibody. Cell populations are usually defined using a '+' or a '−' symbol to indicate whether a certain cell fraction expresses or lacks a CD molecule. For example, a " CD34 +, CD31 −" cell is one that expresses CD34 but not CD31. This CD combination typically corresponds to

5220-588: The detection of initial dementia symptoms and may not communicate accurate information to a physician. Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses. Common supplemental tests include blood tests , thyroid function tests , as well as tests to assess vitamin B12 levels, rule out neurosyphilis and rule out metabolic problems (including tests for kidney function , electrolyte levels and for diabetes ). MRI or CT scans might also be used to rule out other potential causes of

5310-486: The development of drugs to treat a wide range of diseases. A study on patient-derived xenograft mice suggested that CD40 agonists antibodies are promising immunotherapeutic candidates for pediatric B-ALL. Cluster of differentiation The CD nomenclature was proposed and established in the 1st International Workshop and Conference on Human Leukocyte Differentiation Antigens (HLDA), held in Paris in 1982. This system

5400-556: The distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in Alzheimer's disease. Alzheimer's disease (AD) can only be definitively diagnosed with autopsy findings; in the absence of autopsy, clinical diagnoses of AD are "possible" or "probable", based on other findings. Up to 23% of those clinically diagnosed with AD may be misdiagnosed and may have pathology suggestive of another condition with symptoms that mimic those of AD. AD

5490-423: The early stages of Alzheimer's disease. Apathy and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease. Mild cognitive impairment (MCI) is often found to be a transitional stage between normal aging and dementia . MCI can present with a variety of symptoms, and when memory loss is the predominant symptom, it is termed amnestic MCI and

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5580-523: The efficacy of immune checkpoint blockade. This is likely due to the high mutational burden most of these models display, which causes them to respond better to immune checkpoint blockade than human glioma, but is nonetheless relevant information for research in immunomodulatory therapies. CD40 is expressed on B-cell acute lymphoblastic leukemia (B-ALL) cases and a study on patient-derived xenograft mice suggested that CD40 agonists are promising immunotherapeutic candidates for pediatric B-ALL. Hyper-IgM syndrome

5670-440: The example of CD4 and CD8, these molecules are critical in antigen recognition. Others (e.g., CD135 ) act as cell surface receptors for growth factors . Recently, the marker CD47 was found to have anti- phagocytic signals to macrophages and inhibit natural killer (NK) cells. This enabled researchers to apply CD47 as a potential target to attenuate immune rejection . Alzheimer disease Alzheimer's disease ( AD )

5760-462: The fact that people with trisomy 21 (Down syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of Alzheimer's disease by 40 years of age. A specific isoform of apolipoprotein, APOE4 , is a major genetic risk factor for Alzheimer's disease. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in

5850-413: The following are present: no genetic evidence, decline in both learning and memory, two or more cognitive deficits, and a functional disability not from another disorder. The NIA-AA criteria are used mainly in research rather than in clinical assessments. They define AD through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia. Diagnosis in the preclinical stage

5940-449: The fourth text revision of the DSM (DSM-IV-TR). The DSM-5 defines criteria for probable or possible AD for both major and mild neurocognitive disorder. Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD. For major neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if

6030-509: The immune system. CD molecules are utilized in cell sorting using various methods, including flow cytometry . Two commonly used CD molecules are CD4 and CD8 , which are, in general, used as markers for helper and cytotoxic T cells, respectively. These molecules are defined in combination with CD3+, as some other leukocytes also express these CD molecules (some macrophages express low levels of CD4; dendritic cells express high levels of CD8). Human immunodeficiency virus binds CD4 and

6120-412: The individual has genetic evidence of AD or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present. Otherwise, possible AD can be diagnosed as the diagnosis follows an atypical route. For mild neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if there is genetic evidence, whereas possible AD can be met if all of

6210-658: The killing of cancer cells by effector cells . Similarly, ligation of CD40 may lead to cell death in some tumor cells, as it is expressed in all lymphoid malignancies and in a number of carcinomas . There are a number of completed and ongoing clinical trials using agonistic anti-CD40 monoclonal antibodies to elicit an anti-tumor T-cell response via dendritic cell activation. Over the past 20 years, numerous human CD40 monoclonal antibodies have been developed and evaluated in clinical trials due to encouraging variability in cancer animal models. Agonistic anti CD -40-Abs are designed to mimic CD40L by cross-linking CD40 and in this way promoting

6300-458: The macrophage, including reactive oxygen species and nitric oxide , leading to the destruction of ingested microbe. The B cell can present antigens to helper T cells . If an activated T cell recognizes the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40 receptor, causing B cell activation. The T cell also produces IL-2 , which directly influences B cells. As

6390-401: The major producers of amyloid beta that contribute to major extracellular plaque deposition. Alzheimer's disease is also considered a tauopathy due to abnormal aggregation of the tau protein . Every neuron has a cytoskeleton , an internal support structure partly made up of structures called microtubules . These microtubules act like tracks, guiding nutrients and molecules from the body of

6480-399: The major source of this DNA damage. Sleep disturbances are seen as a possible risk factor for inflammation in Alzheimer's disease. Sleep disruption was previously only seen as a consequence of Alzheimer's disease, but as of 2020 , accumulating evidence suggests that this relationship may be bidirectional . The cellular homeostasis of biometals such as ionic copper, iron, and zinc

6570-658: The maturation of DCs and enhancing their antigen presentation ability. This leads to an increase in tumor antigen-specific cytotoxic T cells, which may result in tumor eradication. On the other hand, the preclinical efficacy has not yet been tested in the clinical setting, and none of these monoclonal antibodies have progressed beyond early testing phases. Because of toxicity, the use of CD40 monoclonal antibodies has been limited to suboptimal doses, resulting in inadequate immune activation and antitumor activity. More recently, agonistic CD40 therapy has been shown to decrease T cell cytotoxicity in preclinical glioma models, and in fact affect

6660-409: The molecule. If the molecule has not been well characterized or has only one mAb, it is usually given the provisional indicator "w" (as in " CDw186 "). For instance, CD2 mAbs are reagents that react with a 50‐kDa transmembrane glycoprotein expressed on T cells . The CD designations were used to describe the recognized molecules but had to be clarified by attaching the term antigen or molecule to

6750-492: The most cognitively demanding activities. Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary , which leads to frequent incorrect word substitutions ( paraphasias ). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so

6840-445: The neurotransmitter acetylcholine . The loss of cholinergic neurons noted in the limbic system and cerebral cortex, is a key feature in the progression of Alzheimer's. The 1991 amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21 , together with

6930-406: The overactive immune response. On the other hand, drugs that activate CD40 signaling have shown efficacy in treating cancer by boosting the immune response against tumor cells. CD40 also plays a role in the development of chronic inflammation, and targeting CD40 with drugs has the potential to treat diseases such as Crohn's disease and ulcerative colitis. Overall, CD40 represents a promising target for

7020-582: The person from home care to other long-term care facilities . During the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even

7110-457: The person with Alzheimer's is usually capable of communicating basic ideas adequately. While performing fine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties ( apraxia ) may be present; however, they are commonly unnoticed. As the disease progresses, people with Alzheimer's disease can often continue to perform many tasks independently; however, they may need assistance or supervision with

7200-450: The person's life ( episodic memory ), facts learned ( semantic memory ), and implicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories. Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency , leading to a general impoverishment of oral and written language . In this stage,

7290-519: The relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations. Only 1–2% of Alzheimer's cases are inherited due to autosomal dominant effects, as Alzheimer's is highly polygenic. When the disease is caused by autosomal dominant variants, it is known as early onset familial Alzheimer's disease , which is rarer and has a faster rate of progression. Less than 5% of sporadic Alzheimer's disease have an earlier onset, and early-onset Alzheimer's

7380-594: The reverse process of progressive cognitive impairment . According to one theory, dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which in turn generates in amyloid production and tau hyperphosphorylation . An in vivo study employing genetic mouse models to simulate myelin dysfunction and amyloidosis further reveal that age-related myelin degradation increases sites of Aβ production and distracts microglia from Aβ plaques, with both mechanisms dually exacerbating amyloidosis. Additionally, comorbidities between

7470-843: The risk of cognitive decline and Alzheimer's. Affected people become increasingly reliant on others for assistance, often placing a burden on caregivers . The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioral problems or psychosis due to dementia are sometimes treated with antipsychotics , but this has an increased risk of early death. As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease. It most often begins in people over 65 years of age, although up to 10% of cases are early-onset impacting those in their 30s to mid-60s. It affects about 6% of people 65 years and older, and women more often than men. The disease

7560-809: The risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory , which was previously intact, becomes impaired. Behavioral and neuropsychiatric changes become more prevalent. Common manifestations are wandering , irritability and emotional lability , leading to crying, outbursts of unpremeditated aggression , or resistance to caregiving. Sundowning can also appear. Approximately 30% of people with Alzheimer's disease develop illusionary misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and limitations ( anosognosia ). Urinary incontinence can develop. These symptoms create stress for relatives and caregivers, which can be reduced by moving

7650-842: The role of CD40 in stimulating immune synapses when this interaction happens with CD40L activates dendritic cells to activate antigen specific T cells. This occurs through the upregulation of major histocompatibility complex molecules increased expression of the co-stimulatory molecules CD86/CD80, and upregulation of TNF superfamily ligands on the dendritic cells surface, along with secretion of interleukin-12 (IL-12), which promotes CD8+ T cell activation. Moreover CD40/CD40L interactions provoke antitumor immune responses by increasing tumor cell immunogenic cell death (ICD), APC activation, tumor immunogenicity through upregulation of major histocompatibility complex (MHC) molecules, proinflammatory factor production, co-stimulation of CD4+ and CD8+ T cells, and tumor cell susceptibility to T-cell lysis. In addition

7740-427: The simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia , not the disease itself. In some cases, there is a paradoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity. Alzheimer's disease

7830-399: The stages of lymphocyte differentiation and various functional cell subsets. While doing these experiments, several mAbs were developed against a protein called CD40, a surface receptor of B cells that can be polyclonally activated by a binding ligand. Over time, many features and purposes of the CD40 signaling pathway were discovered, including the discovery of CD40 ligand (CD154/CD40L),

7920-650: The toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis , induces programmed cell death ( apoptosis ). It is also known that A β selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons. Iron dyshomeostasis is linked to disease progression, an iron-dependent form of regulated cell death called ferroptosis could be involved. Products of lipid peroxidation are also elevated in AD brain compared with controls. Various inflammatory processes and cytokines may also have

8010-489: Was found to be associated with a deletion mutation of codon 693 of APP. This mutation and its association with Alzheimer's disease was first reported in 2008, and is known as the Osaka mutation. Only homozygotes with this mutation have an increased risk of developing Alzheimer's disease. This mutation accelerates Aβ oligomerization but the proteins do not form the amyloid fibrils that aggregate into amyloid plaques, suggesting that it

8100-461: Was intended for the classification of the many monoclonal antibodies (mAbs) generated by different laboratories around the world against epitopes on the surface molecules of leukocytes (white blood cells). Since then, its use has expanded to many other cell types, and more than 370 CD unique clusters and subclusters have been identified. The proposed surface molecule is assigned a CD number once two specific monoclonal antibodies are shown to bind to

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