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86-414: Misregulation of CaMKII is linked to Alzheimer's disease , Angelman syndrome , and heart arrhythmia . There are two types of CaM kinases: CaMKII accounts for 1–2% of all proteins in the brain , and has 28 different isoforms . The isoforms derive from the alpha, beta, gamma, and delta genes . All of the isoforms of CaMKII have: a catalytic domain , an autoinhibitory domain, a variable segment, and

172-406: 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

258-470: 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

344-456: 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

430-404: 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

516-409: 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

602-435: 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

688-497: A point mutation of Thr-286 to aspartate, which mimics autophosphorylation and increases kinase activity. These mice failed to show LTP response to weak stimuli, and failed to perform hippocampus-dependent spatial learning that depended on visual or olfactory cues. Researchers speculate these results could be due to lack of stable hippocampal place cells in these animals. However, because genetic modifications might cause unintentional developmental changes, viral vector delivery allows

774-537: 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

860-420: A self-association domain. The catalytic domain has several binding sites for ATP and other substrate anchor proteins. It is responsible for the transfer of phosphate from ATP to Ser or Thr residues in substrates. The autoinhibitory domain features a pseudosubstrate site, which binds to the catalytic domain and blocks its ability to phosphorylate proteins. The structural feature that governs this autoinhibition

946-561: 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

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1032-488: 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

1118-496: 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

1204-529: 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

1290-491: 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

1376-455: Is characterized particularly in many tumor cells, such as a variety of pancreatic, leukemic, breast and other tumor cells. found that CaMK2D is downregulated in human tumor cells. CaMK2G has been shown to be a crucial extracellular signal-regulated kinase in differentiated smooth muscle cells. Alzheimer%27s disease Alzheimer's disease ( AD ) is a neurodegenerative disease that usually starts slowly and progressively worsens, and

1462-435: 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

1548-405: 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

1634-526: 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

1720-547: 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

1806-546: Is infused in postsynaptically in the hippocampal slices and intracellular perfusion or viral expression, there is a two- to threefold increase in the response of the synapse to glutamate and other chemical signals. There is strong evidence that after activation of CaMKII, CaMKII plays a role in the trafficking of AMPA receptors into the membrane and then the PSD of the dendrite. Movement of AMPA receptors increases postsynaptic response to presynaptic depolarization through strengthening

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1892-563: Is initiated when the NMDA receptors are in a local environment with a voltage potential high enough to displace the positively-charged Mg ion from the channel pore. As a result of the channel being unblocked, Ca ions are able to enter into the postsynaptic neuron through the NMDA receptor channel. This Ca influx activates CaMKII. It has been shown that there is an increase in CaMKII activity directly in

1978-406: 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

2064-453: 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,

2150-561: 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

2236-746: Is one of the major forms of CamKII. It has been found to play a critical role in sustaining activation of CamKII at the postsynaptic density. Studies have found that knockout mice without CaMKIIA demonstrate a low frequency of LTP. Additionally, these mice do not form persistent, stable place cells in the hippocampus. CaMK2B has an autophosphorylation site at Thr287. It functions as a targeting or docking module. Reverse transcription-polymerase chain reaction and sequencing analysis identified at least five alternative splicing variants of beta CaMKII (beta, beta6, betae, beta'e, and beta7) in brain and two of them (beta6 and beta7) were first detected in any species. CaMK2D appears in both neuronal and non-neuronal cell types. It

2322-427: 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

2408-513: 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,

2494-497: Is the Threonine 286 residue. Phosphorylation of this site will permanently activate the CaMKII enzyme. Once the Threonine 286 residue has been phosphorylated, the inhibitory domain is blocked from the pseudosubstrate site. This effectively blocks autoinhibition, allowing for permanent activation of the CaMKII enzyme. This enables CamKII to be active, even in the absence of calcium and calmodulin. The other two domains in CaMKII are

2580-484: 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 a person's condition declines, they often withdraw from family and society . Gradually, bodily functions are lost, ultimately leading to death. Although

2666-522: 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

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2752-559: Is the process in which a kinase attaches a phosphate group to itself. When CaMKII autophosphorylates, it becomes persistently active. Phosphorylation of the Threonine 286 site allows for the activation of the catalytic domain. Autophosphorylation is enhanced by the structure of the holoenzyme because it is present in two stacked rings. The close proximity of these adjacent rings increases the probability of phosphorylation of neighboring CaMKII enzymes, furthering autophosphorylation. A mechanism that promotes autophosphorylation features inhibition of

2838-577: Is thought to play an important role in this maintenance. Administration of certain CaMKII blockers has been shown not only to block LTP but also to reverse it in a time-dependent manner. As LTP is thought to underlie the processes of learning and memory, CaMKII is also crucial to memory formation. Behavioral studies involving genetically engineered mice have demonstrated the importance of CaMKII. In 1998, Giese and colleagues studied knockout mice that have been genetically engineered to prevent CaMKII autophosphorylation. They observed that mice had trouble finding

2924-536: 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

3010-452: The PP1 (protein phosphatase I) . This enables CaMKII to be constantly active by increasing the likelihood of autophosphorylation. Calcium/ calmodulin dependent protein kinase II is also heavily implicated in long-term potentiation (LTP) – the molecular process of strengthening active synapses that is thought to underlie the processes of memory. It is involved in many aspects of this process. LTP

3096-428: 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

3182-468: 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

3268-610: 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

3354-619: 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

3440-614: 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

3526-521: 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

Ca2+/calmodulin-dependent protein kinase II - Misplaced Pages Continue

3612-751: 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

3698-533: 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

3784-437: 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

3870-404: 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

3956-523: 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

4042-465: The central nervous system including AMPA, kainic acid and N -methyl- D -aspartic acid (NMDA) channels. In the synapse , these receptors serve very different purposes. AMPA can be used experimentally to distinguish the activity of one receptor from the other in order to understand their differing functions. AMPA generates fast excitatory postsynaptic potentials (EPSP). AMPA activates AMPA receptors that are non-selective cationic channels allowing

4128-539: 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

4214-593: The control; CaMKII continues to be involved in the LTP maintenance process even after LTP establishment. CaMKII is activated by calcium/calmodulin, but it is maintained by autophosphorylation. CaMKII is activated by the NMDA-receptor-mediated Calcium elevation that occurs during LTP induction. Activation is accompanied by phosphorylation of both the alpha and beta-subunits and Thr286/287. LTP can be induced by artificially injecting CaMKII. When CaMKII

4300-478: 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,

4386-591: 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

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4472-517: The different states of activation for the enzyme. Initially, the enzyme is activated; however, autophosphorylation does not occur because there is not enough calcium or calmodulin present to bind to neighboring subunits. As greater amounts of calcium and calmodulin accumulate, autophosphorylation occurs leading to persistent activation of the CaMKII enzyme for a short period of time. However, the Threonine 286 residue eventually becomes dephosphorylated, leading to inactivation of CaMKII. Autophosphorylation

4558-405: 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 the brain . A probable diagnosis is based on the history of

4644-556: 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

4730-423: 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

4816-543: The enhancement of synaptic strength. Sanhueza et al. found that persistent activation of CaMKII is necessary for the maintenance of LTP. She induced LTP in hippocampal slices and experimentally applied an antagonist (CaMKIINtide) to prevent CaMKII from remaining active. The slices that were applied with CaMKIINtide showed a decrease in Normalized EPSP slope after the drug infusion, meaning that the induced LTP reversed itself. The Normalized EPSP slope remained constant in

4902-462: 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

4988-413: 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

5074-452: 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

5160-647: The hidden platform in the Morris water maze task. The Morris water maze task is often used to represent hippocampus-dependent spatial learning. The mice's inability to find the hidden platform implies deficits in spatial learning. However, these results were not entirely conclusive because memory formation deficit could also be associated with sensory motor impairment resulting from genetic alteration. Irvine and colleagues in 2006 showed that preventing autophosphorylation of CaMKII cause mice to have impaired initial learning of fear conditioning. However, after repeated trials,

5246-508: 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

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5332-417: The impaired mice exhibited similar fear memory formation as the control mice. CaMKII may play a role in rapid fear memory, but does not completely prevent fear memory in the long run. In 2004, Rodrigues and colleagues found that fear conditioning increased phosphorylated CaMKII in lateral amygdala synapses and dendritic spines, indicating that fear conditioning could be responsible for regulating and activating

5418-412: 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

5504-412: The kinase. They also discovered a drug, KN-62 , that inhibited CaMKII and prevented acquisition of fear conditioning and LTP. α-CaMKII heterozygous mice express half the normal protein level as the wild-type level. These mice showed normal memory storage in the hippocampus, but deficits in consolidation of memory in the cortex. Mayford and colleagues engineered transgenic mice that express CaMKII with

5590-401: 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

5676-399: 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

5762-585: The mice's genetic material to be modified at specific stages of development. It is possible with viral vector delivery to inject a specific gene of choice into a particular region of the brain in an already developed animal. This, in fact, has been done by Tonegawa group in early 1990s and by Poulsen and colleagues in 2007. Both groups used this method to inject CaMKII into the hippocampus. They found that overexpression of CaMKII resulted in slight enhancement of acquisition of new memories. Drug-induced changes in CaMKII function have been implicated in addiction. CaMKIIA

5848-492: 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

5934-445: 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

6020-582: 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

6106-457: 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

6192-450: 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,

6278-420: The post synaptic density of dendrites after LTP induction , suggesting that activation is a direct result of stimulation. When alpha-CaMKII is knocked out in mice, LTP is reduced by 50%. This can be explained by the fact that beta-CaMKII is responsible for approximately 65% of CaMKII activity. LTP can be completely blocked if CaMKII is modified so that it cannot remain active. After LTP induction, CaMKII moves to

6364-572: The postsynaptic density (PSD). However, if the stimulation does not induce LTP, the translocation is quickly reversible. Binding to the PSD changes CaMKII so that it is less likely to become dephosphorylated. CaMKII transforms from a substrate for Protein Phosphatase 2A (PP2A), which is responsible for dephosphorylating CaMKII, to that of Protein Phosphatase 1. Strack, S. (1997) demonstrated this phenomenon by chemically stimulating hippocampal slices. This experiment illustrates that CaMKII contributes to

6450-561: The process of AMPA receptor exocytosis. Reserve AMPA receptors are embedded in endosomes within the cell. CaMKII can stimulate the endosomes to move to the outer membrane and activate the embedded AMPA receptors. Exocytosis of endosomes enlarges and increases the number of AMPA receptors in the synapse. The greater number of AMPA receptors increases the sensitivity of the synapse to presynaptic depolarization, and generates LTP. Along with helping to establish LTP, CaMKII has been shown to be crucial in maintaining LTP. Its ability to autophosphorylate

6536-519: 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

6622-594: 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

6708-843: 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

6794-809: 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

6880-427: 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

6966-462: 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 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

7052-477: The symptoms – including tumors or strokes. Delirium and depression can be common among individuals and are important to rule out. AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid , better known as AMPA , is a compound that is a specific agonist for the AMPA receptor , where it mimics the effects of the neurotransmitter glutamate . There are several types of glutamatergic ion channels in

7138-490: The synapses. This produces LTP. Mechanistically, CaMKII phosphorylates AMPA receptors at the P2 serine 831 site. This increases channel conductance of GluA1 subunits of AMPA receptors, which allows AMPA receptors to be more sensitive than normal during LTP. Increased AMPA receptor sensitivity leads to increased synaptic strength. In addition to increasing the channel conductance of GluA1 subunits, CaMKII has also been shown to aid in

7224-650: 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

7310-469: The variable and self-association domains. Differences in these domains contribute to the various CaMKII isoforms. The self-association domain (CaMKII AD) is found at the C terminus , the function of this domain is the assembly of the single proteins into large (8 to 14 subunits) multimers The sensitivity of the CaMKII enzyme to calcium and calmodulin is governed by the variable and self-associative domains. This sensitivity level of CaMKII will also modulate

7396-493: 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

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