Inducing agents for Alzheimer’s disease in animal models

AD affects over 55 million people globally, with an annual incidence of 10 million new cases. The main pathological features include amyloid plaques and NFTs, which impair synaptic transmission and cognitive function. Genetic forms, such as familial AD, are more understood, while sporadic AD—affecting 95% of cases—remains elusive. Due to the complexity of AD, animal models are pivotal for studying disease mechanisms and evaluating potential interventions.

Inducing Agents for AD in Animal Models

The review focuses on various agents, their mechanisms of action, and their relevance in mimicking AD pathology in animal models:

Aluminium Chloride (AlCl3)

Aluminium is linked to neurotoxicity and has been identified in high quantities in AD brains. Animal studies with AlCl3 have shown it induces oxidative stress, cholinergic dysfunction, and the formation of amyloid plaques and NFTs. However, results vary depending on dosage and administration route, necessitating further investigation.

Streptozotocin (STZ)

STZ, a naturally occurring antibiotic, is widely used to model sporadic AD in rodents. It impairs brain metabolism, induces oxidative stress, and promotes tau hyperphosphorylation, leading to neurodegeneration. The ICV administration of STZ consistently produces cognitive deficits, closely resembling human AD pathology.

Trimethyltin (TMT)

TMT is a neurotoxin that induces significant neuronal damage in the cortex and hippocampus, key areas affected in AD. TMT models exhibit cognitive impairments similar to AD but do not replicate amyloid and tau pathologies, limiting their utility as comprehensive AD models.

Lipopolysaccharide (LPS)

LPS, a bacterial endotoxin, is used to induce neuroinflammation in animals. This model is valuable for studying inflammation’s role in AD progression, as LPS administration leads to increased amyloid deposition and neuron loss. However, it does not mimic other key AD pathologies like tau tangles.

Scopolamine

Scopolamine blocks acetylcholine receptors, resulting in cognitive impairments akin to those seen in AD. Animal models using scopolamine are simple to administer and reproducible, although they focus on cholinergic dysfunction and lack amyloid or tau pathology.

Aβ Injections

Direct injections of amyloid-beta (Aβ) peptides into animal brains simulate amyloid plaque deposition, a hallmark of AD. Studies have shown that Aβ injections impair learning and memory, mimicking AD's cognitive symptoms, although this method does not address the full spectrum of AD pathogenesis.

D-Galactose

Excessive D-galactose induces oxidative stress and inflammation, simulating aging and AD-like symptoms in animals. Combined with agents like AlCl3, D-galactose accelerates neurodegeneration and cognitive decline, providing a useful model for studying early-stage AD.

Colchicine

Colchicine disrupts microtubule function, leading to cognitive impairments similar to AD. Although it mimics certain inflammatory processes seen in AD, colchicine models do not fully capture the complexity of AD pathology.

Okadaic Acid

Okadaic acid inhibits protein phosphatases, leading to tau hyperphosphorylation and neuronal death. This model is particularly useful for studying tau-related pathologies in AD, although it is limited by its toxicity and non-specific effects on brain function.

Ibotenic Acid

Ibotenic acid causes significant neuronal damage and inflammation, closely resembling the neurodegenerative processes seen in AD. However, the invasive nature and high mortality rates of ibotenic acid models limit their widespread use.

Future Directions

Despite advancements, no single animal model fully replicates AD's complexity. Most models mimic intermediate to late-stage AD, while early-stage models are lacking. Future research should focus on developing models that capture the gradual cognitive decline and diverse pathological events of AD. Standardizing administration techniques and optimizing the dosage of inducing agents will enhance the reproducibility of results.

Conclusions

Animal models remain crucial for understanding AD's molecular and cellular underpinnings. While current models help explore specific aspects of the disease, more comprehensive models are needed to study early-stage AD and test potential therapies. Continued research will help establish more reliable models that better reflect AD pathology and provide insights into potential treatments.

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https://www.xiahepublishing.com/2572-5505/JERP-2023-00028

The study was recently published in the Journal of Exploratory Research in Pharmacology.

Journal of Exploratory Research in Pharmacology (JERP) publishes original innovative exploratory research articles, state-of-the-art reviews, editorials, short communications that focus on novel findings and the most recent advances in basic and clinical pharmacology, covering topics from drug research, drug development, clinical trials and application.

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