Probing the biology of Alzheimer's disease in mice

Abstract

Alzheimer's disease (AD), the most common cause of dementia among the elderly, may either represent the far end of a continuum that begins with age-related memory decline or a distinct pathobiological process. Although mice that faithfully model all aspects of AD do not yet exist, current mouse models have provided valuable insights into specific aspects of AD pathogenesis. We will argue that transgenic mice expressing amyloid precursor protein should be considered models of accelerated brain aging or asymptomatic AD, and the results of interventional studies in these mice should be considered in the context of primary prevention. Studies in mice have pointed to the roles of soluble beta-amyloid (Abeta) oligomers and soluble tau in disease pathogenesis and support a model in which soluble Abeta oligomers trigger synaptic dysfunction, but formation of abnormal tau species leads to neuron death and cognitive decline severe enough to warrant a dementia diagnosis.

Figure 1

APP and its major proteolytic products. Cleavage of APP by α-, β-, γ-, and ε-secretases produces secreted amino-terminal fragments, carboxyl-terminal polypeptides, and Aβ. (Ma et al. (2007) Involvement of beta-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. Proc Nat’l Acad Sci U S A. 104(19):8167–72. “Copyright (2007) National Academy of Sciences, U.S.A.”)

Figure 2

Regional hypometabolism in APP transgenic mice and people at risk for AD. MRI and [¹⁸F]-FDG-PET scans of (A) a control subject and (B) a carrier of a presenilin-1 mutation associated with familial autosomal dominant AD, 27 years before mean age of onset of dementia in her family. Bilateral hypometabolism of parietal cortex and medial temporal lobe is evident on PET in the absence of atrophy on MRI. C) Regional cerebral glucose utilization, monitored with [¹⁴C]2-deoxyglucose, in the cortex and hippocampus of a neophobic transgenic FVB/N mouse expressing human APP with a disease-linked mutation. Compared to its non-transgenic littermate, the transgenic mouse shows decreases in glucose utilization in cerebral cortex and hippocampus. Pseudocolored images of autoradiograms of coronal sections through cerebral cortex, hippocampus, and anterior brainstem; warmer colors represent greater glucose uptake. D) Magnified view of (C) showing hippocampus and overlying cerebral cortex. (A,B) reprinted by permission of the Society of Nuclear Medicine from: Mosconi L, Sorbi S, de Leon MJ, et al. Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease. J Nucl Med. 2006; 47(11): 1778–86. Figure 2. (C,D) reprinted from Neuron 15(5), Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, Xu S, Eckman C, Younkin S, Price D, et al., Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins, Pages 1203–18, Copyright (1995), with permission from Elsevier.

Figure 3

APP transgenic mice model asymptomatic Alzheimer’s disease. APP transgenic mice exhibit functional abnormalities similar to those observed in people at risk for Alzheimer’s disease, but do not display the loss of neurons seen in people clinically diagnosed with Mild Cognitive Impairment or Alzheimer’s disease.

Figure 4

Ab initiates a disease process that might progress to a stage of cognitive impairment, but tau mediates cognitive dysfunction. In this hypothetical scheme, Aβ*56 (see Section 4.1) and perhaps other Aβ oligomers, cause synaptic dysfunction that manifests as subtle cognitive deficits in APP transgenic mice and in people in the asymptomatic phase of AD. Toxic Aβ oligomers surrounding plaques locally damage neurons, but their effects on cognition are unknown (see Section 4.2). Abnormal tau processing triggered by pathological forms of Aβ in AD, and by mutations in tau transgenic mice, cause loss of synapses and neurons and cognitive deficits severe enough to warrant a diagnosis of Mild Cognitive Impairment (MCI) or AD. The effects of NFTs, rather than soluble pathological forms of tau, are unknown (see Section 4.4). It is also not known whether the same effector molecules/mechanisms responsible for Aβ-induced synaptic and cognitive dysfunction trigger tau abnormalities or whether a separate pathway is involved.