I think that the best model system available depends on your purpose.

For example, if you are interested in identifying treatments that mitigate plaque/tangle formation, then the 3x transgenic mouse may be best.

However, if you want to understand AD-associated cellular mechanisms "upstream" of plaques and tangles, that mouse would be close to useless.

Considering how little we really know about cellular mechanisms underlying AD, I personally prefer a cellular approach to whole animal (transgenic) models, but if you are interested in identifying biomarkers that might serve as diagnostics, you would need the latter.

For cellular models, the choice should also consider your target of interest. For example, it is very hard to induce tau toxicity in cell line cultures, but relatively easy to cause such toxicity with in situ tau overexpression or expression of tauopathy mutant tau isoforms. In my lab, we generated a cellular tauopathy model in the mid 1990s simply by microinjecting plasmids encoding wt human tau into lamprey giant reticulospinal neurons. I think it was the first time human tau had ever been shown to be toxic on its own, and we did it essentially by accident! This result was later replicated in transgenic mice using both overexpression and (more usually) tauopathy mutant tau isoforms. I'm guessing that this is because tau toxicity is generated in the context of structures (e.g. synapses) that never develop in cell lines, but I don't really know.

That said, if you want to look at tau toxicity in cell culture, perhaps you should use either primaries or inducible stable lines expressing tau mutant species known to be toxic in cell lines.

I'm sure that other cellular targets of interest for AD will have their own issues that affect the choice of model.

I would like to put in a plug for non-murine animal models as well. Mice are expensive, and the regulatory issues can be daunting if you don't have a lot of institutional resources. The lamprey served me well, but it's a pain to use!  I'd look into Drosophila models if I were starting out today - many important insights into disease mechanism have come from there.

Bottom line - you have some background reading to do before you invest a lot of resources in any one model!

I hope that helps......

Experimental procedure: Intracerebroventricular injection of streptozotocin model

Wistar rats are used for evaluating the Anti-Alzheimer's effect. The animals are divided into the following groups according to the design of the experiment

1. Sham-operated group (Sham Control), 2.CSF Control group (CSF Control) that received bilateral ICV injection of artificial CSF (ACSF) (10 μl on each side) as the solvent of STZ 3. STZ injected group (STZ Control) which received ICV injection of STZ

(10 μl on each side) and the drug treated group.

Intracerebroventricular injection of streptozotocin:

The rats are anesthetized and placed in a Stoelting stereotaxic

apparatus (Ugo Basile, Italy) (incisor bar −3.3 mm, ear bars

positioned symmetrically). The scalp is cleaned with iodine

solution, incised on the midline and a burr hole is drilled through

the skull 0.8 mm posterior to bregma, 1.4 mm lateral to saggital

suture, and 3.4 mm beneath the surface of brain, according to the

stereotaxic atlas (Paxinos and Watson, 1986). STZ and test drug treated

groups are given a bilateral ICV injection of freshly dissolved STZ

(3 mg/kg) in cold artificial CSF at a volume of 10 μl on each side. The

injection is repeated on day 3. In the CSF Control group, only

artificial CSF (120 mM NaCl; 3 mM KCl; 1.15 mM CaCl2; 0.8 mM

MgCl2; 27 mM NaHCO3; and 0.33 mM NaH2PO4 adjusted to pH 7.2)

is ICV injected. Post-operatively, special care is undertaken until

spontaneous feeding is restored.

Behavioral and biochemical parameters are evaluated on Day 21.

Just to clarify, are you specifically looking for a rodent model rather than a human model system? It depends on how "simple" you want to make it. Anything with animal models ends up being complicated in my experience! Do you want an in vivo system or an in vitro system?

Dear Dr. Claire Cox

Thanks so much for your answer. I am looking for a rodent or invitro models which need no gene manipulations.

It is OK how difficult it could be.

Have you looked into the SAMP8 mouse?

Prior to the availability of transgenic animals, rodent lesion models were often used as behavioral simulations of Alzheimer's disease. This could involve for example, lesions to the entorhinal cortex or hippocampus, which are regions that degenerate in Alzheimer's disease. Some investigators used colchicine, to simulate neurofibrillary tangles. You may get some memory deficits characteristic of Alzheimer's disease, as well as the production of neurotrophic factors, glycosaminoglycans and gliosis similar to what has been observed in human amyloid plaques. There is also an axonal sprouting response that has been proposed to occur in Alzheimer's disease, perhaps compensatory, perhaps pathological. Obviously this is not a perfect model because it is not degenerative, but it really depends on your purpose and the question that you are trying to address. The literature on hippocampal and entorhinal cortex lesions is extensive, and spans across decades. I have four papers focusing on this, but you can find many, many more:

http://www.ncbi.nlm.nih.gov/pubmed/?term=entorhinal+cortex+woods+ag

There is also an extensive literature focusing on in vitro beta-amyloid toxicity in cultured primary neurons or cell lines (such as PC12 cells). This is a fairly expensive technique however, particularly if you want to set up primary neuronal cell culture. It also requires a cell culture facility.

I know that you are asking for a perfect model, but I think there is really no "perfect animal model" for human disease. The perfect model is the human disease state, and you might settle for an animal model if it meets your objectives and constraints (in your case, no gene manipulation). I don't know what your objective is, however that is something to keep in mind. Good luck!

Since we do not know the cause of Alzheimer's disease, it is not possible to model it at this time. It is unfortunate that many investigators are assuming they are studying the disease through artificially over expressing proteins in mice that are suspected to be involved in humans. At best, these "models" provide an indication of possible effects of proteins when produced at levels above that present in the Alzheimer's brain. It remains an open question whether the results point to relevant pathologic effects in human beings.

It is possible to get neural stem cells derived iPS cells from Alzheimer's disease patients to model the disease in vitro as these are commercially available. They don't have genetic manipulation as such, but do have mutations seen in Alzheimer's Disease. This has the advantage that it is from a human system and they can be transplanted into an in vivo system e.g. into rat brain.

Animal models for Alzheimer's are not something I have had direct experience with, but I think some others have given you good advice!

As Alisa said, there really isn't a perfect model, but there can be the most appropriate one depending on what you want to examine and your budget!

Thank you all for your wise Guides and helpful advice!

I'm currently working on A-beta plus ibotenic acid model of Alzheimer's Disease. It's working well.....

There is no such thing as a "perfect" animal model of AD. Even with the newest /best AD models, our proteomic analyses reveal only a few changes consistent with AD post-mortem human brain (mostly Abeta and Tau).

I've worked with 5xFAD mice as well as, and the only thing they phenocopy are the Abeta plaques...

But until we discover the critical initial mechanisms underlying AD pathogenesis, we won't be able to create a "perfect" animal model.

I will suggest to read this paper and find your good model if you dont have transgenic mouse option. If you have 3x transgenic mouse model that will be best. Also known as triple transgenic mouse model of Alzheimer disease.

Hi!

It is hard to say which model if perfect; however, I suggest you two models that you can decide which one you prefer to choice.

First As Claire said iPS in would be a good model for assessing the neurodegenerative disease including Alzheimer and Parkinson. ” It is possible to get neural stem cells derived iPS cells from Alzheimer's disease patients to model the disease in vitro as these are commercially available. They don't have genetic manipulation as such, but do have mutations seen in Alzheimer's disease. This has the advantage that it is from a human system and they can be transplanted into an in vivo system e.g. into rat brain; Claire said.

Second, you can infect the fibrils of A-beta directly to the mouse brain as it has been done previously for Parkinson’ disease. Please take a look at: doi:10.1093/brain/awt037, DOI: 10.1126/science.1227157 and www.jem.org/cgi/doi/10.1084/jem.20112457

Hello there,

I am not sure yet, however you could follow this suggestion too.

You can infect the cell culture by the fibrils of A-beta. It is so easy and inexpensive. We are carrying out such work regarding the Parkinson' disease study. As a matter of fact, as you know alpha-synuclein which is involved in Parkinson' is intercellular; however, A-beta which is the most protein involved in Alzheimer is intracellular. In fact it is further present between the cells. So, you can carry out the fibrillation process for A-beta easily and then add the fibrils on the grown cells (the cells which are always used as a model in Alzheimer disease). Subsequently, follow up the cells by standard test for assessing whether the fibrils spread through cells and whether it has penetrated to the cells or transferred from cell to cell. This phenomenon is already proved for alpha-synuclein, which is called prion like transmission.

You can find more information in this article: Patrik Brundin, Ronald Melki and Ron Kopito, 2010, Prion-like transmission of protein aggregates in neurodegenerative diseases. NATURE REVIWES | Molecular cell Biology. Vol (11) 301-307.

Also there are several articles exist regarding the Parkinson’ disease in such case but I do not read the articles in this case concerning the Alzheimer disease. There must be articles regarding the Alzheimer disease too.

I think that the best model system available depends on your purpose.

For example, if you are interested in identifying treatments that mitigate plaque/tangle formation, then the 3x transgenic mouse may be best.

However, if you want to understand AD-associated cellular mechanisms "upstream" of plaques and tangles, that mouse would be close to useless.

Considering how little we really know about cellular mechanisms underlying AD, I personally prefer a cellular approach to whole animal (transgenic) models, but if you are interested in identifying biomarkers that might serve as diagnostics, you would need the latter.

For cellular models, the choice should also consider your target of interest. For example, it is very hard to induce tau toxicity in cell line cultures, but relatively easy to cause such toxicity with in situ tau overexpression or expression of tauopathy mutant tau isoforms. In my lab, we generated a cellular tauopathy model in the mid 1990s simply by microinjecting plasmids encoding wt human tau into lamprey giant reticulospinal neurons. I think it was the first time human tau had ever been shown to be toxic on its own, and we did it essentially by accident! This result was later replicated in transgenic mice using both overexpression and (more usually) tauopathy mutant tau isoforms. I'm guessing that this is because tau toxicity is generated in the context of structures (e.g. synapses) that never develop in cell lines, but I don't really know.

That said, if you want to look at tau toxicity in cell culture, perhaps you should use either primaries or inducible stable lines expressing tau mutant species known to be toxic in cell lines.

I'm sure that other cellular targets of interest for AD will have their own issues that affect the choice of model.

I would like to put in a plug for non-murine animal models as well. Mice are expensive, and the regulatory issues can be daunting if you don't have a lot of institutional resources. The lamprey served me well, but it's a pain to use!  I'd look into Drosophila models if I were starting out today - many important insights into disease mechanism have come from there.

Bottom line - you have some background reading to do before you invest a lot of resources in any one model!

I hope that helps......