Transgenic models of Alzheimer's disease: learning from animals

Abstract

As the scope of the problem of Alzheimer's disease (AD) grows due to an aging population, research into the devastating condition has taken on added urgency. Rare inherited forms of AD provide insight into the molecular pathways leading to degeneration and have made possible the development of transgenic animal models. Several of these models are based on the overexpression of amyloid precursor protein (APP), presenilins, or tau to cause production and accumulation of amyloid-beta into plaques or hyperphosphorylated tau into neurofibrillary tangles. Producing these characteristic neuropathological lesions in animals causes progressive neurodegeneration and in some cases similar behavioral disruptions to those seen in AD patients. Knockout models of proteins involved in AD have also been generated to explore the native functions of these genes and examine whether pathogenesis is due to loss of function or toxic gain of function in these systems. Although none of the transgenic lines models the human condition exactly, the ability to study similar pathological processes in living animals have provided numerous insights into disease mechanisms and opportunities to test therapeutic agents. This chapter reviews animal models of AD and their contributions to developing therapeutic approaches for AD.

FIG. 1.

The amyloid hypothesis of Alzheimer's pathogenesis suggests that altered processing of APP due to genetic and environmental influences causes a cascade of events leading to neuronal dysfunction and death.

FIG. 2.

Amyloid precursor protein cleavage by β- and γ-secretases leads to the production of Aβ, the primary component of senile plaques in AD. Circled molecules have been used in transgenic mouse models to study AD pathogenesis. Overexpression of APP causes plaque formation in mice and coexpressing either β- or γ-secretase components with APP accelerates plaque formation. Aβ increases neurofibrillary tangle formation in tau overexpressing mice. Studies of ApoE knockout and transgenic mice indicate that this molecule may be involved in both Aβ deposition and clearance. Reducing LRP in mouse models increases Aβ deposition, indicating a role for LRP in clearance or degradation of Aβ. Similarly, overexpression of TGF-β1 reduces plaque burden in APP mice implicating it in Aβ clearance.

FIG. 3.

Overexpression of mutant human APP in Tg2576 mice (a) causes age-related deposition of amyloid into plaques and cerebral amyloid angiopathy (labeled blue with methoxy X-O4; blood vessels are filled with Texas Red). The amyloid pathology in these mice closely resembles that seen in the AD brain as shown with 10D5 immunostaining (b). Scale bars: 50 μm.