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Model organisms

Drug discovery in dementia: the role of rodent models

Nature Reviews Drug Discovery volume 5, pages 956–970 (2006)Cite this article

Key Points

  • Alzheimer's disease (AD), including both early-onset familial and late-onset senile dementia of the Alzheimer type, accounts for the major proportion of dementia cases and neurodegenerative diseases.

  • AD is characterized by progressive cognitive, functional and behavioural impairment, evolving into a dramatic loss of most cortical and subcortical functions, and ultimately death. The major pathological hallmarks include amyloid plaques, neurofibrillary tangles and neuronal cell loss.

  • Valid animal models for AD could help to further unravel underlying degenerative processes and discover therapeutic strategies to alleviate and/or prevent this devastating condition. We describe the major rodent models of AD and evaluate their effectiveness for drug discovery research.

  • For a therapeutic intervention to slow down or halt disease progression — that is, to be disease-modifying — it must interfere with a central pathophysiological pathway.

  • Rodent models have acquired a strong position in the evaluation of the preventive and disease-modifying efficacy of potential therapeutics because they rapidly develop symptoms and/or pathology, allow the assessment of large groups of subjects, improve accessibility to early-stage CNS changes and enable time-linked observations.

  • Non-cognitive symptoms represent a major source of physical and psychological caregiver burden often motivating institutionalization of the patient. Animal models mimicking these symptoms are indispensable tools for evaluating new psychopharmacological strategies

  • We empahsize the need for validation of all new models and thorough standardization of procedures, good knowledge of strains, compounds and paradigm characteristics, and skilled personnel.

  • The implementation of a multidisciplinary approach combining valid animal models with new technologies improving biomarker profiling and early diagnosis of dementia subtypes, as well as prediction of patient-specific treatment outcome, will create new paths for improved treatment and prevention of AD.

Abstract

Recent advances in the understanding of the pathophysiological mechanisms underlying Alzheimer's disease have pointed to novel strategies for drug development. Animal models have contributed considerably to these advances, and will have a key role in the evaluation of therapeutics that could have the potential not just to alleviate the dementia associated with Alzheimer's disease, but to modify the disease process. Here, we summarize and critically evaluate current rodent models of dementia, and discuss their role in drug discovery and development.

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Figure 1: APP processing and APP mutations associated with early-onset Alzheimer's disease.
Figure 2: Theoretical possibilities of treatment outcome in Alzheimer's disease.
Figure 3: General treatment schedules in preclinical evaluation.
Figure 4: Examples of biomarkers of pathology in Alzheimer's disease.
Figure 5: Assessing disease-modifying efficacy in rodent models of Alzheimer's disease.

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Acknowledgements

This work was financed by the Fund for Scientific Research–Flanders, Agreement between the University of Antwerp and the Institute Born-Bunge, Neurosearch Antwerp, the Antwerp Medical Research Foundation, and the Thomas Riellaerts Research fund.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Laboratory of Neurochemistry and Behaviour, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, Wilrijk, 2610, Belgium

    Debby Van Dam

  2. Department of Neurology / Memory Clinic, Middelheim General Hospital, ZNA, Lindendreef 1, Antwerp, 2020, Belgium

    Peter Paul De Deyn

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Glossary

Anomia

Impaired recall of words with no impairment of comprehension or the capacity to repeat the words.

Aphasia

Loss or impairment of the ability to produce and/or comprehend language.

Perseveration

Uncontrollable repetition of a particular response — for example, a word, phrase or gesture — despite the absence or cessation of a stimulus.

Paraphasia

The production of unintended syllables, words or phrases during the effort to speak.

Agnosia

Loss of ability to recognize objects, persons, sounds, shapes or smells while the specific sense is not defective.

Prosopganosia

Disorder of face perception with impairment of the ability to recognize faces.

Apraxia

Loss of the ability to execute or carry out learned movements, despite having the desire and the physical capacity to perform the movements.

Nucleus basalis of Meynert

Basal forebrain cholinergic neurons that primarily project to the cerebral cortex and amygdala.

Early-onset Alzheimer's disease

(EOAD). Refers to cases of AD in which disease onset occurs before the age of 65. EOAD represents approximately 5% of all AD cases.

Cholinomimetic

Having an action similar to that of acetylcholine.

Amyloid-derived diffusible ligands (ADDLs)

Soluble Aβ oligomers that directly inhibit long-term potentiation, and therefore synaptic plasticity, and which have been linked to synaptic loss and reversible memory failure in trangenic animal models.

Disease-modifying therapy

Therapy that can slow or halt the progression of a disease by interacting with a central pathophysiological pathway(s).

Memory consolidation

Molecular memory consolidation refers to molecular processes by which long-term conductivity of synapses is affected by training. Network consolidation describes the idea that episodic memories are initially stored in the hippocampus and are slowly moved to the neocortex.

Procedural memory

Refers to the memory for skills and procedures that are often not easily put into words and can be used without conscious recollection (for example, learning to ride a bike or touch typing).

Declarative memory

The aspect of (human) memory that stores facts and events that can be consciously recalled. It includes episodic memory and semantic memory, which refer to the memory of personal events and the memory of facts, meanings and understanding, respectively.

Theranostics

The identification and prediction of specific phenotypic characteristics associated with well-characterized biomarker profiles and monitoring or even prediction of the efficacy of disease-modifying drugs for a specific human condition.

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Van Dam, D., De Deyn, P. Drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov 5, 956–970 (2006). https://doi.org/10.1038/nrd2075

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