**7. Conclusions**

Anothercharacteristicofthe3xTg‐ADmouseisthatthebrainregionsseverelyaffected,including the hippocampus, entorhinal cortex, amygdala, neocortex, and some subcortical areas such as basal forebrain where the acetylcholine (Ach) neurotransmitter is altered in the brains of individuals with mild AD due to low choline acetyltransferase (ChAT) activity [165–167].

The 3xTg‐AD mouse has fewer ChAT‐immunopositive neurons in the Meynert nucleus (primary source of cholinergic neurons), as well as a reduced density of ChAT‐positive cholinergic fibers projecting to the primary motor cortex and the CA1 area of the hippocampus [168]. These cognitive dysfunctions are caused by massive loss of cholinergic neurons in the anterior basal brain, the area most vulnerable to the development of the pathological charac‐ teristics associated with AD. Alterations in cholinergic neurotransmission in the patients' neocortex and hippocampus are associated with the early stages of memory loss [168]. We also found a 50% reduction in nest‐building quality (a task controlled by the hippocampus), associated with a significant increase in damaged neurons in the CA1 hippocampal area (26%) compared to wild‐type mice [170]. The decreased ability to carry out activities of daily living (humans) or to perform nest building correctly (3xTg‐AD mice) are behavioral symptoms that can be studied and related to anatomical and morphological signs in the complex Alzheimer's

A variety of animals can serve as experimental models of AD, which are valuable tools for the design of new therapeutic strategies and to explore some other aspects of the disease, as some specimens develop amyloid plaques in their brain and cognitive dysfunctions similar to those of AD. Like humans, dogs develop amyloid plaques in their brains with advancing age, and some specimens suffer sporadic cases of Alzheimer's disease, age‐related cognitive impair‐ ment with loss of short‐term memory or working memory, changes in behavior, irritability, incontinence, and orientation problems [171]. Sarasa cloned and sequenced the canine APP, finding it virtually identical to human APP, including the peptide sequence corresponding to β‐amyloid peptide. They analyzed the presence and distribution of amyloid plaques in the brains of healthy young and old dogs with severe cognitive dysfunction. With specific antibodies against AB40 and AB42, they found that the old demented animals had many

A nontransgenic rodent *Octodon degus*, which develops hallmarks of AD, could be a natural model to understand how sporadic AD, between 12 and 36 months of age, develop the accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age‐ related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic

Sparks and Schreurs proposed studying AD in rabbits fed a diet rich in cholesterol and copper. These animals develop amyloid plaques in their brains and deficiencies in learning complex tasks. They exhibit increased immunoreactivity to amyloid β in neurons, the presence of extracellular plaques in the meninges, microgliosis, apoptosis, vascular activation of SOD,

disease syndrome.

208 Update on Dementia

plasticity [172].

**6.1. Sporadic models for Alzheimer's study**

amyloid and more mature plaques than older control dogs [163].

This review poses a historical overview of the pathology of Alzheimer's disease and provides an up to date of its features. Then, a molecular and histological follow‐up of the proteins most strongly associated with this pathology is delivered. Finally, the diverse molecular and cellular current hypotheses seeking to disentangle the mechanisms of Alzheimer's disease and supported by research in animal models are analyzed. These models have been extremely useful in elucidating the mechanisms of Alzheimer's disease, including the numerous factors and conditions that contribute to the pathogenesis, which may have important implications providing new insight for current and future strategies to treat Alzheimer's disease and to reduce or delay its onset by preventing infection, inflammation and amyloidosis.
