Alzheimer's disease
Alzheimer’s disease is the most common cause of dementia in the world. This debilitating disease affects memory, thinking and behaviour. Symptoms eventually grow severe enough to interfere with daily tasks. As such, it has a physical, psychological, social, and economic impact, not only on people with the disease, but also on their careers, families and society at large.
Although Alzheimer’s mainly affects older people – half of the population over 85 is affected compared to 1 in 10 over 65 - it is not a normal part of ageing. It is not just a disease of old age, younger people can develop forms of Alzheimer’s too.
After decades of research into Alzheimer’s, researchers know a whole lot more about the disease but there is still much that remains unknown, and a truly effective treatment and cure have yet to be been found. Current treatments slow the symptoms and improve quality of life but cannot stop disease progression. Today, there is a worldwide effort under way to find better ways to treat the disease, delay onset and prevent it from developing altogether. Most of this research happens in animals.
Animal studies and animal experiments provide opportunities for understanding how Alzheimer's disease affects the brain, and for studying potential new treatments. Certain abnormalities resembling those of Alzheimer's disease can be found in primates, ie humans, apes and monkeys (1), and in certain strains of mice (2,3,4).
Pathology
Genetic Aspects
Current Treatments
Improving Diagnostics
Lifestyle Issues
Animal models of Alzheimer's disease
References
Pathology
Alzheimer's disease has long been associated with the development of amyloid-beta (Aß) plaques and tangles of fibrous Tau proteins in the brain. It is still unclear whether these structures are the source of damage or a symptom of something deeper, but regardless, they have been the focus point of most curative research.
Despite their simplicity relative to humans, fruit flies have formed an important part of understanding the development of tau tangles. The flies can also be altered genetically to produce clearly observable traits when tau tangles form, making them a useful for screening potential new compounds or breaking down the tangles (3,5).
Unfortunately, despite the efforts and investments of large pharmaceutical companies, treatments targeting amyloid plaques have all failed in clinical trials (5). While some drugs have managed to clear the plaques, they do not appear to slow the degeneration of cognitive ability (6). The tau protein tangles, however, do appear to correlate better with brain function and much recent research is aimed at removing these. (1)
Alzheimer’s disease has also been referred to as ‘Type III diabetes’. Animal experiments have indeed linked the cognitive degeneration to impaired brain metabolism, particularly, insulin resistance in brain cells. Loss of insulin receptors in rat brain cells produces similar symptoms to Alzheimer’s disease7 and similar effects have also been seen in rats and rabbits that have diabetes8. Following the work in animals, research has shown that adults with Alzheimer's disease tend to show dysregulated insulin functioning in peripheral tissues (2) and that brain tissue with plaques show little response9 to the presence of insulin.
The found epidemiological connection between diabetes, obesity, and dementia has meant new opportunities to further understand – and treat - these conditions. (3)
Genetic Aspects
While there are some rare cases of single genetic defects resulting in hereditary early-onset Alzheimer’s disease, the disease is more than often multifactorial. Research has shown that those who have a parent or sibling with Alzheimer's are more likely to develop the disease than those who do not have a first-degree relative with Alzheimer’s, but family history isn’t necessarily to blame, environmental factors also play their part.
More than often, genes tend to have only a minor effect on a person’s risk factor (10). Researchers have identified both risk and deterministic hereditary Alzheimer's genes. Risk genes increase the likelihood of developing a disease but do not guarantee it will happen whereas deterministic genes directly cause a disease, guaranteeing that anyone who inherits one will develop a disorder. These last ones are quite rare and only account for 1% or less of reported cases, but have had an enormous impact on the science.
The discovery of these deterministic genes has provided important clues to help understand the disease. All of these genes tend to affect processing or production of beta-amyloid proteins, the prime suspects in the decline and death of brain cells. They have also been used to make genetically modified mice that are affected by the disease.
Mice that were genetically engineered to have Alzheimer's have notably enabled scientists to show that the Aß enters the brain by riding piggyback on a non-toxic molecule called RAGE, overproduced in Alzheimer's mice, and which freely crosses the blood-brain barrier (15). Research and animal tests using genetically modified mice has also shown how one particular version of the human APP gene leads to build up of damaging deposits in the brain (11).
Genetically engineered mice have been made that lack the enzyme that makes amyloid. There are compounds that block the enzyme, and these may be clinically useful if they are safe in humans (1,2,13).
As an important research tool, mouse models enable the exploration of genetic, environmental, and behavioral aspects of Alzheimer’s, as well as make it possible to test drug candidates before human studies. As research progresses, more precise, and more informative mouse models continue to see the light of day. Scientists try to develop new animal models to characterize different stages of the disease, and that encapsulate multiple aspects of the human form of the disease. (1)
This video demonstrates some of the techniques used to monitor the progress and treatment of mice with Alzheimer-like symptoms. (2)
The 2018 Brain Prize was awarded to Bart De Strooper (London and Leuven), Michel Goedert (Cambridge), Christian Haass (Munich) and John Hardy (London) for their groundbreaking research on the genetic and molecular basis of Alzheimer’s disease. The research of these four European scientists, some of which has used GM animals, has revolutionised our understanding of the changes in the brain that lead to Alzheimer´s disease and related types of dementias.
Current Treatments
Alzheimer’s disease is complex, and it is therefore unlikely that any one drug or other intervention will successfully treat it in all people. Still, in recent years, scientists have made tremendous progress in better understanding Alzheimer’s and in developing and testing new treatments, including several medications that are in late-stage clinical trials.
Also no cure exists, several drugs help manage symptoms, which can provide people with comfort, dignity, and independence for a longer period of time. The main class of drugs used are known as cholinesterase inhibitors. These prevent the degradation of the neurotransmitter acetylcholine, a brain chemical believed to be important for memory and thinking, which helps reduce or control some cognitive and behavioral symptoms. The importance of acetylcholine was first noted in 1914 and later research on frogs and horses revealed its use in the body16.
The newest medication, aducanumab (FDA approved in 2021), is the only disease-modifying medication, which targets the underlying causes of a disease, currently approved to treat Alzheimer’s. It is a human antibody, or immunotherapy, that was shown in animal studies (9,10,11) to target the protein beta-amyloid and helps to reduce amyloid plaques, which are brain lesions associated with Alzheimer’s. It is the first therapy to demonstrate that removing amyloid from the brain is reasonably likely to reduce cognitive and functional decline in people living with early Alzheimer’s. Research is still ongoing to see if its effect lasts over time. The European Medicines Agency (EMA) has not yet approved aducanumab, and it remains unavailable for people living with Alzheimer's disease in Europe and in the UK.
Improving Diagnosis
Current diagnosis of Alzheimer's disease relies largely on documenting mental decline, at which point, Alzheimer's has already caused severe brain damage. Researchers hope to discover an easy and accurate way to detect Alzheimer's before these devastating symptoms begin. The hope is, future treatments could then target the disease in its earliest stages, before irreversible brain damage or mental decline has occurred.
Research on new strategies for earlier diagnosis is among the most active areas in Alzheimer's science. Experts believe that biomarkers offer one of the most promising solutions, but improvements in brain imaging, cerebrospinal fluid tests, blood tests, or even genetic risk profiling could be key.
Animal models are essential for finding clues to markers of disease, as researchers know that the animals are affected by the condition and can look for markers for the abnormalities in the blood for example.
Early diagnosis might also help treatment. Researchers are now starting to recognize that, for current clinical trials on Alzheimer’s disease (in particular of anti-amyloid monoclonal antibodies), one of the reasons for failures may actually be the inclusion of subjects without Alzheimer disease, that may account for up to 30% out of the target population in prodromal phase or early dementia trials (1,12,13,14).
Lifestyle Issues
There is increasing evidence that some lifestyle factors are linked to the development of Alzheimer's disease. Many of these are potentially modifiable and include smoking, physical activity, education, social engagement, cognitive stimulation, and diet. Current evidence can based on observational data, but also animal science.
Several animal studies confirm the clinical impression that healthy lifestyles offer a degree of protection. Physical activity – five months use of a running wheel – appears to inhibit brain changes in Alzheimer’s mice, enhancing learning ability and decreasing the deposition of amyloid in the brain (24).
Obese people are at higher risk of developing Alzheimer’s, and this finding has been replicated in mice: in two studies, Alzheimer’s mice developed 30–50% less plaque when fed on calorie-restricted or low carbohydrate diets (25,26). Aged, genetically engineered mice predisposed to Alzheimer’s disease that were fed DHA fish oil, an omega-3 fatty acid, developed significantly less amyloid protein (27).
Traumatic brain injury also predisposes to Alzheimer's disease, and research in mice showed that this is causal: mice that received repeated head trauma developed plaque-like deposits faster than mice that suffered a single or no injury (21).
Some reports have also found the bacterium Chlamydia pneumoniae in the brains of 90% of Alzheimer's patients at autopsy, although this has been difficult to reliably reproduce in later studies (22). Scientists have found that spraying it into the noses of mice caused plaque formation (23).
Animal models of Alzheimer's disease
Experimental models of Alzheimer’s disease (AD) are critical to gaining a better understanding of pathogenesis and to assess the potential of new therapeutic approaches. To date, the vast majority of experimental models are animal models, almost exclusively consisting of transgenic mice that express human genes that result in the formation of amyloid plaques (by expression of human APP alone or in combination with human PSEN1) and neurofibrillary tangles (by expression of human MAPT). The most commonly used experimental animal models are transgenic mice that over express human genes associated with familial Alzheimers (FAD) that result in the formation of amyloid plaques.
To date, over 170 genetically modified mouse (1) models containing Alzheimer’s-linked mutations have been generated to study this progressive neurodegenerative disorder, and in many instances these mice have yielded insights into the underlying pathogenic mechanisms (2,4,5,6,7). But because of the way they were first made possible, most of these mouse models were, up to recently, better representations of familial early onset genetic forms of Alzheimer’s disease, not other, probably more common, forms of Alzheimer’s disease. This has meant that the track record of success in clinical trials thus far has been very poor. Researchers are now trying to model the more common late-onset sporadic forms of the disease to hopefully increase understanding of this disease (3,8,18). A greater understanding of the strengths and weakness of each of the various models and the use of more than one model to evaluate potential therapies could increase the success of therapy translation from preclinical studies to patients. Results generated from experimental models can be exceptionally informative about specific aspects of Alzheimer’s disease if researchers are aware of the limitations associated with each model.
A smaller number of transgenic rat models of Alzheimer’s disease have also been developed (19). Transgenic rats have a number of potential advantages over transgenic mice; they are more similar to humans in their physiological, morphological and genetic characteristics, their larger brain makes CSF collection, electrophysiology and imaging easier and they have a richer behavioral phenotype, making more complex behavioral testing possible. Three transgenic rat models have been well characterized in the literature. (4,20,21,22)
Other models have included invertebrate animals such as Drosophila melanogaster and Caenorhabditis elegans, as well as vertebrates such as zebrafish; however, given these models’ greater distance from human physiology they are less extensively used (5,15,16,17).
References
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277874/
8. https://www.nature.com/articles/s41467-021-22624-z
10. https://alzres.biomedcentral.com/articles/10.1186/s13195-021-00809-4
11. https://www.jneurosci.org/content/37/17/4430
12. https://pubmed.ncbi.nlm.nih.gov/31211176/?dopt=Abstract
13. https://pubmed.ncbi.nlm.nih.gov/33185922/
14. https://www.nature.com/articles/d43978-022-00075-4
15. https://pubmed.ncbi.nlm.nih.gov/25697708
16. https://pubmed.ncbi.nlm.nih.gov/26756400/
17. https://pubmed.ncbi.nlm.nih.gov/25071820/
20. https://pubmed.ncbi.nlm.nih.gov/23575824/
21. https://pubmed.ncbi.nlm.nih.gov/20164597/
22. https://pubmed.ncbi.nlm.nih.gov/18504134/
References
References to previous version of this page
- Geula C, Wu C-K, Saroff D, Lorenzo A, Yuan M, Yankner BA (1998) Aging renders the brain vulnerable to amyloid ß protein neurotoxicity Nature Medicine 4, 827
- Games D, Adams D, Alessandrini R, Barbour R et al (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F ß amyloid precursor protein Nature 373, 523
- Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G, (1996) Correlative memory deficits, Aß elevation, and amyloid plaques in transgenic mice Science 274, 99
- Capsoni S, Ugolini G, Comparini A et al (2000) Alzheimer-like neurodegeneration in aged antinerve growth factor transgenic mice Proc Nat Acad Sci 97 6826
- http://www.newscientist.com/article/mg20727701.400-alzheimers-unlocked-new-keys-to-a-cure.html
- http://www.sciencedirect.com/science/article/pii/S1474442210700430
- http://www.newscientist.com/article/mg21528805.800-food-for-thought-eat-your-way-to-dementia.html?page=1
- Bitel CL, Kasinathan C, Kaswala RH, Klein WL, Frederikse PH (2012) Amyloid-β and tau pathology of Alzheimer's disease induced by diabetes in a rabbit animal model. J Alzheimers Dis. 32(2):291-305. doi: 10.3233/JAD-2012-120571.
- Talbot K, Wang HY, Kazi H, et al. (2012) Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 122(4):1316-38. doi: 10.1172/JCI59903.
- Bird TD, Genetic aspects of Alzheimer disease. Genet Med. (2008) 10(4):231-9. doi: 10.1097/GIM.0b013e31816b64dc.
- Wengenack TM, Curran GL, Poduslo JF (2000) Targeting Alzheimer amyloid plaques in vivo. Nat Biotech 18 868
- Ohno M, Sametsky EA, Younkin LH et al (2004). BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease Neuron 41, 27
- Luo Y, Bolon B, Kahn S et al (2001) Mice deficient in BACE1, the Alzheimer's ß-secretase, have normal phenotype and abolished ß-amyloid generation Nature Neuroscience 4, 231
- Reddy PH, McWeeney S, Byung S. Park BS et al (2004) Gene expression profiles of transcripts in amyloid precursor protein transgenic mice: up-regulation of mitochondrial metabolism and apoptotic genes is an early cellular change in Alzheimer's disease Human Molecular Genetics 13, 1255
- Deane R, S, Yan SD, Submamaryan RK et al (2003) RAGE mediates amyloid-ß peptide transport across the blood-brain barrier and accumulation in brain Nature Medicine 9, 907
- H. H. Dale and H. W. Dudley. (1929) The presence of histamine and acetylcholine in the spleen of the ox and the horse. The Journal of Physiology 68, 97-123
- Holtzmann DM, Bales KR, Tenkova T et al (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease Proc Nat Acad Sci 97 2892
- Connor JM, Darracq MA, Roberts J, Tuszynskit MH (2001) Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation Proc Nat Acad Sci 98, 1941
- DeMattos RB, Bales KR, Cummins DJ et al (2002) Brain to Plasma Amyloid-ß Efflux: a Measure of Brain Amyloid Burden in a Mouse Model of Alzheimer's Disease Science 295, 2264
- Wyss-Coray T, Loike JD, Brionne TC et al (2003) Adult mouse astrocytes degrade amyloid-ß in vitro and in situ Nature Medicine 9, 453
- Uryu K, Laurer H, McIntosh T, et al (2002) Repetitive mild brain trauma accelerates Aß deposition, lipid peroxidation, and cognitive impairment in a transgenic mouse model of Alzheimer amyloidosis J Neurosci 22, 446
- Shima K, Kuhlenbäumer G, Rupp J (2010) Chlamydia pneumoniae infection and Alzheimer's disease: a connection to remember?. Med Microbiol Immunol 199(4):283-9. doi: 10.1007/s00430-010-0162-1
- Little CS, Hammond CJ, MacIntyre A, Balin BJ and Appelt DM (2004) Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice Neurobiology of Aging 25, 419
- Adlard, PA Perreau VM, Pop V, Cotman CW (2005) Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease. J. Neurosci. 25, 4217
- Wang J, Ho L, Qin W et al (2005) Caloric restriction attenuates β-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J.
- Patel NV, Gordon MN, Connor KE et al (2005) Caloric restriction attenuates Aβ-deposition in Alzheimer transgenic models. Neurobiology of Aging 26, 995
- Lim GP, Calon F, Morihara T (2005) A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J. Neurosci. 25, 3032
- Praticò D, Uryu K, Leight S (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis J Neurosci 21, 4183
- Weggen S, Eriksen JL, Das P et al (2001) A subset of NSAIDs lower amyloidogenic Aß42 independently of cyclooxygenase activity Nature 414, 212
- http://www.alzinfo.org/research/alzheimers-research-aimed-at-prevention
- http://www.nih.gov/news/pr/dec2004/od-20.htm
- http://www.nature.com/news/2004/040726/full/news040726-4.html
- De Strooper B, Woodgett J (2003) Alzheimer's disease: Mental plaque removal Nature 423, 392
- http://taurx.com/lmtx-for-ad.html
- http://www.alzheimers.org.uk/site/scripts/documents_info.php?documentID=1094&pageNumber=3
Last edited: 13 September 2022 10:28