Modes of Aβ toxicity in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is reaching epidemic proportions, yet a cure is not yet available. While the genetic causes of the rare familial inherited forms of AD are understood, the causes of the sporadic forms of the disease are not. Histopathologically, these two forms of AD are indistinguishable: they are characterized by amyloid-β (Aβ) peptide-containing amyloid plaques and tau-containing neurofibrillary tangles. In this review we compare AD to frontotemporal dementia (FTD), a subset of which is characterized by tau deposition in the absence of overt plaques. A host of transgenic animal AD models have been established through the expression of human proteins with pathogenic mutations previously identified in familial AD and FTD. Determining how these mutant proteins cause disease in vivo should contribute to an understanding of the causes of the more frequent sporadic forms. We discuss the insight transgenic animal models have provided into Aβ and tau toxicity, also with regards to mitochondrial function and the crucial role tau plays in mediating Aβ toxicity. We also discuss the role of miRNAs in mediating the toxic effects of the Aβ peptide.

Fig. 1

Histopathological and genetic features of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Memory impairment characterizes AD at a clinical level, and the presence of amyloid (Aβ) plaques and phospho-tau-containing neurofibrillary tangles (NFTs) in brain at a histopathological level. A unifying feature of the plaques and tangles is that their major proteinaceous components, Aβ and tau, respectively, are fibrillar. Plaques are scarce in FTD. The prominent feature in FTD is a behavioral impairment, with memory functions often being preserved until late in disease. Compared to AD, FTD is a highly heterogeneous group of related dementias, as reflected both by the function of the mutated genes, by the proteins that are deposited as insoluble aggregates, and by the clinical syndromes, with language and behavioral variants known. A subset of FTD, known as frontotemporal lobar degeneration with tau deposits (FTLD-T) or FTD with Parkinsonism linked to chromosome 17 (FTDP-17), is characterized by tau inclusions. The first FTD mutations were identified in the tau-encoding MAPT gene causing FTLD-T. Mutations have been subsequently identified in the PGRN gene encoding progranulin, and in the VCP gene encoding valosin-containing protein. TDP-43 is the deposited protein, and these deposits are shared with motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS). Fused in sarcoma (FUS) is another pathological protein that has been identified in a small subset of patients with either ALS or a form of FTD. In familial AD (FAD), mutations have been identified in the APP gene encoding the amyloid precursor protein from which Aβ is derived by proteolytic cleavage, and in the genes encoding presenilin 1 and 2 (PSEN1 and PSEN2), which form part of the Aβ cleavage machinery. In AD, no mutations have been identified in the tau-encoding MAPT gene

Fig. 2

Modes of Aβ toxicity as illustrated for the signaling through the NMDA (N-methyl d-aspartate) receptor (NMDAR). Tau is perceived as an ‘axonal’ protein, although a fraction of it is present in dendrites. Tau functions in targeting the kinase Fyn to this compartment. Fyn then phosphorylates the NMDAR subunit NR2B, thereby mediating complex formation of NMDARs with the post-synaptic density protein 95 (PSD95). The over-activation of the NMDAR complex (excitotoxicity) results in excessive nitric oxide (NO) levels. This causes down-stream protein misfolding and aggregation, as well as mitochondrial fragmentation. The toxic signaling pathway also involves the release of mitochondrial cytochrome c (Cyt c) and the activation of down-stream caspases as well as the formation of reactive oxygen species (ROS). The excitotoxicity complex mediates Aβ’s toxic functions and subsequent neurodegeneration, a process that depends on the presence of tau. Inset: Components of the mitochondrial respiratory chain itself are targets of Aβ and tau and, together, these toxic entities synergistically impair mitochondrial functions