Relevance of Transgenic Mouse Models to Human Alzheimer Disease

Abstract

During the past 2 decades, the elucidation of susceptibility and causative genes for Alzheimer disease as well as proteins involved in the pathogenic process has greatly facilitated the development of genetically altered mouse models. These models have played a major role in defining critical disease-related mechanisms and in evaluating novel therapeutic approaches, with many treatments currently in clinical trial owing their origins to studies initially performed in mice. This review discusses the utility of transgenic mice as a research tool and their contributions to our understanding of Alzheimer disease.The most common cause of dementia, AD 2 accounts for 60 -70% of all dementia cases and afflicts Ͼ15 million individuals worldwide. The disorder is characterized by severe memory loss, with episodic memory being particularly impaired during the initial phases. At present, the disorder is not curable. Most AD cases occur sporadically (SAD), although inheritance of certain susceptibility genes enhances the risk. A small minority of AD cases (Ͻ1%) is inheritable (referred to as FAD) and is caused by mutations in genes encoding APP, PS1, or PS2. Pathological Hallmarks of ADDefinitive diagnosis of AD occurs during post-mortem examination upon detection of two hallmark pathologies. The first is amyloid plaques, which consist of A␤. The length of A␤ can vary, but a 42-amino acid variant is considered neurotoxic because of its propensity to readily aggregate into oligomers and fibrils. All mutations associated with FAD affect the aggregation and/or production of A␤, which is sequentially cleaved from the APP holoprotein, first by an enzyme known as BACE (beta-APP-cleaving enzyme) and then by an enzymatic complex known as ␥-secretase, in which the presenilins form the catalytic core (1). FAD-associated mutations in APP cluster around the ␤-secretase cleavage site (e.g. Swedish mutation), in key amino acids affecting its ability to aggregate (e.g. Arctic and Dutch mutations), or around the ␥-secretase cleavage site, which increases production of the longer A␤42 peptide (e.g. London mutation). PS mutations play a similar role by favoring production of A␤42 at the expense of A␤40. In vitro experiments and transgenic mice have shown us that the aggregation state of A␤ is crucial, that it can also accumulate intraneuronally, and that it can mediate a diverse range of pathological effects on cellular function (2).The second pathological hallmark is the appearance of intraneuronal aggregates composed of the microtubule-associated protein tau. Hyperphosphorylation of tau leads it to dissociate from the microtubules and aggregate within the axoplasm as NFTs (3). Furthermore, tau dissociation leads to a reduction in microtubule stability and impaired axonal transport, ultimately leading to neuronal dysfunction and loss of synapses and subsequent retrograde degeneration (4). Mutations in the gene for tau (MAPT) are not associated with AD but cause FTDP-17 (frontal temporal dementia with parkinsonism 17), showing that disruption ...

Mouse Models for Studying the Formation and Propagation of Prions

“…In fact, it is somewhat inappropriate to refer to these as "models" of prion disease because prion-challenged mice actually develop bona fide prion disease and recapitulate all of the neuropathological and biochemical hallmarks of the human and animal diseases. In contrast, mouse models of Alzheimer disease (AD) are non-ideal because they typically develop senile plaques and cognitive deficits, but not the neurofibrillary tangles and associated neuron loss seen in AD patients (11). Similarly, mouse models of Parkinson disease (PD) develop a neurodegenerative disease, but the brains of spontaneously sick mice do not contain the Lewy bodies that are found in the brains of patients with PD (12).…”

Aqueous extract of lavender (Lavandula angustifolia) improves the spatial performance of a rat model of Alzheimer’s disease

“…There are 2 forms of AD, including early onset AD that is related with genetic factors, and late onset common form of disease [2] that is associated with aging [3] . AD is characterized by intracellular accumulation of neurofibrillary tangles (NFTs) and extracellular deposition of beta amyloid (A) plaques [4] .…”

Calretinin Interneurons are Early Targets of Extracellular Amyloid-β Pathology in PS1/AβPP Alzheimer Mice Hippocampus

“…Transgenic mice overexpressing mutant familial Alzheimer's disease (AD) genes [amyloid-β protein precursor (AβPP), presenilin-1 (PS1), and PS2] are widely used to study AD-related pathology progres-sion and the mechanisms underlying neuronal dysfunction [1,2]. However, the pathogenesis of AD is highly complex and these mice display some, but not all, neuropathological lesions of the disease.…”