Understanding Alzheimer’s Disease Through Animal Models

Types of Animal Models Used in Alzheimer’s Research

Question:

Describe about the treatment of Alzheimer’s disease?

The discussion topic here is focused on application of animal models to understand the concept of Alzheimer’s disease and its underlying pathogenesis. In researches of human disease, animal models help the researchers with better understanding of the disease process without harming or adding risk to an actual human individual. No transgenic models mimics exact human behavior, yet the capacity to study comparable pathological progressions inside living individuals have offered various insights into ailment mechanisms and chances to analyze therapeutic agents. Alzheimer’s is considered as a common form of dementia, which causes complications with behavior, thinking and memory (Zarka, 2011). Indications develop slowly and become worse eventually and also start interfering with the daily activities. In a lay man language this disease can also be termed as memory loss and loss of other intellectual capabilities that are severe enough to obstruct daily life activities (Holford, 2005). It is not considered as a normal measurement of aging, yet greatest identified risk aspect is rising age and most of the affected individuals are 65years old or even older. Alzheimer’s affected individual generally survives for almost eight years after their indications become noticeable. Current treatments related with the Alzheimer’s cannot stop this disease from progressing. These therapies can temporarily slow down the worsening affects of dementia indications and develop patients’ life quality and also the life quality of the care provider.

Recent advancements of biotechnology have helped the scientists immensely to think about such concept of designing animal models which can assist to understand and analyze the basic reason behind a particular human disease. With the help of recombinant DNA technology, the concept of knockout mice has been originated. These are considered as the most important animal models for examining the function of genes. These genes are sequenced, but their functions are not determined. In knockout mice the gene of interest is inactivated purposely and after that the difference is observed by comparing with the normal pathology. Thus, this type of animal model helps researchers to predict probable function of that particular gene of interest. Over expression of amyloid precursor proteins contribute to the accumulation and production of beta amyloid into plaques or neurofibrillary tangles. By manipulating genes production of the distinctive neuro-pathological lesions inside animal gives raise to the progressive neurodegeneration and sometimes related behavioral disruptions are identified within AD patients. Knock out models of AD related proteins have been developed to illustrate the indigenous role of the genes and analyze if pathogenesis is because of loss of genetic function or poisonous increase of function within the system.

Pathology of Alzheimer’s disease comprises three consistent neuropathological characteristics. These are amyloid-rich senile plaques, neuronal degeneration and neurofibrillary tangles. Acetylcholine is considered as a vital neurotransmitter in the portions of brain, which participate in the formation of memory. Loss of acetylcholine activity shows an association with Alzheimer’s disease severity. Drugs that are used to treat this disease work by inhibiting the activity of acetylcholinesterase (Casadesus, 2011). These inhibitors block esterase arbitrated metabolism of acetylcholine to acetate and choline. This gives rise to the increased amount of acetylcholine within synaptic cleft and augmented acetylcholine availability for presynaptic and postsynaptic muscarinic and nicotinic acetylcholine receptors. Apolipoprotein E4 on 19chromosome shows late commencement of Alzhimer’s disease. Apolipoprotein E4 allele increase the risk and reduce the age of commencement of this disease in dose associated fashion. Transgenic animal models have helped the researchers to obtain the basic and the most important information associated with Alzheimer’s disease.

Pathology of Alzheimer’s Disease

Alzheimer’s disease is said to be common reason of dementia among the aged people, who are 65years old and even older (Perry, 2013). It affects almost 10% people over 65years of age and 50% people over 85years of age. Almost 4million Alzheimer’s patients are present in the United States itself and fourth leading reason of death in United States (Alz.org, 2015). Overwhelmingly most of the AD patients are cared at home by their friends and family members. Annual treatment of this disease costs almost $100billion (Alz.org, 2015).

Projected prevalence of Alzheimer’s disease; Progress of Alzheimer’s disease; source: (Samakashvili et al., 2011)

Alzheimer’s disease develops through different stages; source: (Samakashvili et al., 2011)

Alzheimer’s disease is considered as a neurological brain disorder, which is irreversible and progressive. According to the scientists no single cause is present for this disease. It is probably the consequence of a blend of inter-associated factors, comprising genetic aspects that are inherited along with family lines and influences from the environment that range from an early head injury to educational level to individual’s understanding near the beginning in life. Now-a-days, life style factors are also thought to be associated with this disease, for instance: dietary habits, high cholesterol, and higher level of blood pressure that may influence individual’s risk of this disease. It is a common type of dementia tracked by dementia with Lewy bodies and vascular dementia (Kwon and Choi, 2013). Assessment of this disease includes informant history, functional and physical assessment, brain imaging and focused labs. Initial treatments objectives comprise improve life quality, function maximization by developing behavior, mood and cognition. Treatment can be applied non-pharmacological and pharmacological interventions. Community resourced need to be applied to support the care providers, family members and patients (Gauthier, 2012).

Non pharmacological factors include cognitive enhancement, individual therapy and group therapy, regular appointments, communication with care providers and family members, safety attention and environmental modification (Birbaumer, 2011). Pharmacological factors include cholinesterase inhibitors, for example: galantamine, donepezil, rivastigmine; other cognitive enhancers comprise ginko biloba, vitamin E, NSAIDs and estrogen; antipsychotics and antidepressants. Symptom management of this disease may include sun-downing, hallucinations, delusions or psychoses, hypersexuality, sleep disturbances and aggression.  

Stage1. Normal: mentally healthy individual.

Stage2. Aged forgetfulness: individuals more than 65years of age experience subjective criticisms of functional and cognitive complications (Dash and Villemarette-Pittman, 2005).

Stage3. Little cognitive impairment: the capability to carry out executive works becomes compromised; for those individuals who are working their performance may turn down.

Stage4. Mild Alzheimer’s: most general functioning deficit is decreased ability to deal with complicated activities of daily life, such as: capability to manage accounts and to arrange foods for guests and many more.

Stage5. Moderate Alzheimer’s: shows a decrease in the capacity to select appropriate clothing to wear for different weather conditions and daily occasions or situations.

Stage6. Moderately serious Alzheimer’s: capacity to carry out basic daily living activities becomes compromised.

Stage7. Severe Alzheimer’s: the sufferers need continuous support with basic daily living activities for survival.

Prevalence and Treatment of Alzheimer’s Disease

The diagnostic tests for this disease include medical history: an interview session to recognize pre-medical complications; physical examination: assessments of heart, lungs, sight and hearing, pulse reading, blood pressure and temperature; neuropsychological examinations: physicians use different assessment tools to evaluate problem-solving,  memory, vision-motor coordination, attention and theoretical thinking, for example: calculating simple calculation without the help of any pen, paper or calculator and brain imaging scan: CT scans and MRI illustrate the brain structure and are applied to exclude blood clots or tumors inside the brain as the cause  for indications.

Most of the genes associated with human disease are owned by evolutionary conserved paths that are found in simple organisms, for example: Drosophila melanogaster and Caenorhabditis elegans. These pathways and genes of the simpler organisms can be pharmacologically and genetically manipulated to understand mechanism and function in a better way and also the way these genes are linked with the pathogenesis of various ailments (Birbaumer, 2011). These manipulations can be carried out frequently in worms and flies than in mammals. And can be performed quite rapidly and produce high quality information which are translatable to the mammalian organizations. Other qualities are also present which make these organisms typically well suited for human disease study. For example: constructing in vivo disease structures which can help clarify basic systems underlying  disease, because in vitro examinations do not always represent normal physiological complexity related to different diseases. Animal models, especially invertebrate models are comparatively inexpensive, have little lifespan, easy to experiment with and often have stereotypical and well characterized development. Precisely understanding the etiopathogenic systems of different neurodegenerative disorders are considered as crucial step for improving disease modifying medicines that are capable to prevent the disease emergence or slow disease progression. Animal replicas contribute to amplify the knowledge on the neurodegerative disease pathophysiology. These animal models mimic various aspects of stated disease, in addition to the main symptoms and histopathological lesions.

Though the advanced animal models have helped greatly to understand the Alzheimer’s disease pathogenesis, lack of knowledge regarding the cause of this disease makes it complicated to structure an AD featuring model, which hinders the characterization and discovery of efficient drugs. At present, most employed animal prototypes are developed depend on recognized genetic mutations associated with the Alzheimer’s disease. Nevertheless, almost more than 90% cases are sporadic and the fundamental causes are not known (Casadesus, 2011). Hence, the genetic based models do not summarize all the features associated with sporadic Alzheimer’s disease and do not even cover all the factors, which may influence the etiopathogenesis of sporadic Alzheimer’s disease, for example: apolipoprotein E. Other complicating factors are that AD animal models do not display wide-ranging neuronal cell loss that is observed in human Alzheimer patients.

Amyloid beta or Aβ is closely associated with the pathogenesis of AD; hence AD rodent models are designed by intracerebral infusion of amyloid beta peptides. Direct intracerebral amyloid beta peptide injection causes memory deficit and learning deficits, along with neuropathological lterations, which resemble human Alzheimer’s disease, microglial activation, inflammation and restricted loss of cells (Lee and Lim, 2010). The infusion rodent model allows scientists to administer identified levels of specific amyloid beta species of recognized length and sequence, before waiting for aging process for the construction of pathological alterations within transgenic animal models. Infusion models are very much helpful for pre-clinical testing of drugs as the models can give experimental outcomes, comprising the pathology of plaque in a time-frame of few weeks.

Nevertheless the administered Aβ concentration is higher than Aβ concentration found within the brain of Alzheimer affected individuals, leading to the alterations of the brain, which surpass the aging effct on Alzheimer’s disease progression. On the other hand, genetically altered mice over expressiong amyloid beta 42 or APP accumulate amyloid beta plaques and soluble amyloid beta oligomers in an age dependant way (Jagust, 2009). These APP models show progressive amyloid beta deposition in neuritic plaques, diffuse plaques, astrocytosis, cerebral amyloid angiopathy, neurotransmission alterations, mild hippocampal atrophy, microgliosis, behavioral and cognitive deficits.

The article “Neurodegeneration and Alzheimer’s disease: the lesson from tauopathies” by G. Sorrentino and V. Bonavita (2007) is one of the very significant articles that critically examines the Amyloid Cascade Hypothesis which is generally considered to be a decisive factor in Alzheimer’s disease (Sorrentino and Bonavita, 2007). This article further throws light on the apoptotic mechanisms that are considered as the connecting links which Aβ deposition and proteolysis of tau.

The primary objective of this article is to situate the morphology factors which characterize the more general neurodegen. The hypothesis of Amyloid Cascade basically suggests that the main event in the Alzheimer’s disease is the deposition of the fibrils of β-amyloid protein (Aβ). The authors objected to this hypothesis on the ground that this particular hypothesis is weak when correlated to the plaque load and severity of dementia.

According to the authors the correlation between dementia and synaptic loss depict that the Alzheimer’s disease may be considered under the synaptic failure. The authors further state that the significant factor that can be extracted from the studies of mutations in the domestic form of fronto-temporal dementia would be the mutation which is enough to cause neuronal loss. Most of the data observations suggest one such model of Alzheimer’s disease which as a result of the overproduction and minimized clearance of Aβ deposition. This however is considered as an early event in pathogenic sequence. There is wide amount of data available that suggest that the apoptotic mechanism tend to represent the link between proteolysis of tau and the Aβ deposition. Jointly, all these observations indicate that in the model of AD where the excessive production or the minimized clearance of the Aβ results in a flow of events which lead to direct neuronal loss or loss resulting from changes in the tau.

With regard to experimenting with the animal models there exists a huge line of evidence that join to show the soluble oligomers of Aβ, however it does not demonstrate the insoluble amyloid fibrils. These soluble oligomers of Aβ are sometimes responsible for the synaptic dysfunction that generally takes place in the brains of the animal models.

The article conducted a study to further show that the tau expression had given NFT pathology certain amount of neuronal loss as well as behavioral deficiency. Nevertheless, it needs to be kept in mind that when this source of tau was concealed there was an improvement in the memory that was observed when there was a progress in the NFT pathology. As a result of these observations, in the animal model the neuro – degeneration is observed to be caused due to an oligomeric or a “pre-tangle” tau and not by the NFTs themselves. Looking from this point of NFT can be considered as an indicator of damage which has already been done rather than the direct pathogen which is viewed as the Aβ plaques by most scientists. Hence it can be stated that the article even though deals primarily with the missing link also closely analyses the results on the animal models.

Scientists Peter T. Nelson et al. (2009) have conducted an animal model study to reveal a complicated association between cognitive impairment and neuropathology in Alzheimer’s disease (Nelson, Braak and Markesbery, 2009). It is known worldwide that neurofibrillry tangles and plaques are pathological hallmarks of this disease. Controversies are present about the application of present AD diagnostic criteria and whether neurofibrillry tangles and plaques are involved in cognitive impairment. According to them neither pathological nor clinical features for Alzheimer’s disease develop in a direct manner. They have discussed about patients with medical dementia with no amyloid plaques and neurofibrillry tangles and also if individuals with no cognitive impairment can have severe Alzheimer’s type pathological assessments at autopsy. The clinicopathological studies need suppositions regarding pathologoical substrates. They have suggested that neurofibrillry tangles and plaques may not be pathogenetic. These abnormalities could also be a neuroprotective response to different disease stimuli, for example: inflammation or oxidative stress (Lefterov, 2009). Neither the inflammatory brain complication nor oxidative stresses have been demonstrated to stimulate neurofibrillry tangles in animal models. All the nervous cells and non-nerve cells may react to inflammation and oxidative stress, sometimes with different extent. The researchers have interpreted qualitative pathological evaluations and genetic evidence of Alzheimer’s brains, typically the pathology of the neurofibrillry tangles, which appears to invade upon and distort normal cell components to specify toxic than other protective function. They have concluded that the association of cognitive impairment along with tangles and plaques with is complicated in Alzheimer’s but rational. Soluble oligomeric amyloid beta species formed by 1-30 amyloid beta amino acids associate better than the plaques along with cognitive impairment in transgenic mice that are Alzheimer’s affected and humans (Lefterov, 2009). The loss of synaptic responses which might be brought about by neurotoxic effect of soluble amyloid beta oligomers and tau pathology is said to be directly associated with cognitive impairment. Mice that overproduce amylod beta protein do not exhibit neurofibrillary tangles. Nevertheless, amyloid beta pathology can trigger kinases, down-regulate phosphatases and damage the degradation of tau. These mechanisms lead to tau pathology. As a result, great challenges are present further on to develop next generation animal models to efficiently assist the treatment and prevention of neurodegenerative diseases.

References

Alz.org, (2015). Latest Facts & Figures Report | Alzheimer’s Association. [online] Available at: https://www.alz.org/alzheimers_disease_facts_and_figures.asp [Accessed 27 Feb. 2015].

Birbaumer, N. (2011). Alzheimer’s disease patients’ cognitive functions are enhanced following a new non-invasive non-pharmacological treatment. Alzheimer’s & Dementia, 7(4), p.S669.

Casadesus, G. (2011). Handbook of animal models in Alzheimer’s disease. Amsterdam: IOS Press.

Dash, P. and Villemarette-Pittman, N. (2005). Alzheimer’s disease. New York, N.Y.: Demos.

Gauthier, S. (2012). Pharmacological treatment of Alzheimer’s disease. Alzheimer’s & Dementia, 8(4), p.P2.

Holford, P. (2005). Alzheimers prevention plan.

Jagust, W. (2009). Will Neuroimaging help us understand Alzheimer’s disease?. Alzheimer’s & Dementia, 5(4), p.P1.

Kwon, J. and Choi, N. (2013). Binswanger-type vascular cognitive impairment no dementia (VCIND) and vascular dementia (VaD). Alzheimer’s & Dementia, 9(4), pp.P788-P789.

Lee, C. and Lim, H. (2010). Altered visuospatial working memory process in patients with Alzheimer’s disease: fMRI investigation. Alzheimer’s & Dementia, 6(4), p.S285.

Lefterov, I. (2009). Role of Abca1, ApoE and ApoA-I in Alzheimer’s disease pathogenesis: Lessons from complex animal models. Alzheimer’s & Dementia, 5(4), p.P168.

Nelson, P., Braak, H. and Markesbery, W. (2009). Neuropathology and Cognitive Impairment in Alzheimer Disease. Journal of Neuropathology and Experimental Neurology, 68(1), pp.1-14.

Perry, G. (2013). Alzheimers disease. Amsterdam: IOS Press.

Samakashvili, S., Ibáñez, C., Simó, C., Gil-Bea, F., Winblad, B., Cedazo-Mínguez, A. and Cifuentes, A. (2011). Analysis of chiral amino acids in cerebrospinal fluid samples linked to different stages of Alzheimer disease. ELECTROPHORESIS, 32(19), pp.2757-2764.

Sorrentino, G. and Bonavita, V. (2007). Neurodegeneration and Alzheimer’s disease: the lesson from tauopathies. Neurological Sciences, 28(2), pp.63-71.

Zarka, H. (2011). Alzheimers. [Kbh.]: Korridor.