Intracellular amyloid-β in Alzheimer's disease

Key Points

  • This Review examines the current evidence supporting a role for intracellular amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease. Intracellular Aβ accumulation appears to be an early event in the disease, and may be a source for extracellular deposits as the disease progresses.

  • Aβ can be produced within cells or taken up from extracellular sources through receptor binding and subsequent internalization. This leads to accumulation within endosomes, multivesicular bodies, lysosomes, mitochondria, the endoplasmic reticulum and trans-Golgi network, and the cytosol.

  • Oligomeric Aβ assembly states have been implicated as the critical pathological species. Aβ oligomerization may commence within cells, possibly through membrane interactions, and these Aβ oligomers may act intracellularly to cause neuronal dysfunction, or pass into the extracellular space.

  • Intracellular Aβ in transgenic mouse models of Alzheimer's disease is associated with cognitive deficits, tau phosphorylation, neuronal loss and synaptic dysfunction.

  • Various treatments and paradigms affect intracellular Aβ, including aging, docosahexaenoic acid, insulin, learning, stress and the Alzheimer's disease risk factor allele APOE*ε4.

Abstract

The primal role that the amyloid-β (Aβ) peptide has in the development of Alzheimer's disease is now almost universally accepted. It is also well recognized that Aβ exists in multiple assembly states, which have different physiological or pathophysiological effects. Although the classical view is that Aβ is deposited extracellularly, emerging evidence from transgenic mice and human patients indicates that this peptide can also accumulate intraneuronally, which may contribute to disease progression.

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Figure 1: APP proteolysis.
Figure 2: Sites of cellular Aβ production.
Figure 3: Pathological effects of intraneuronal Aβ.

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Acknowledgements

We thank M. Blurton-Jones and A. Parachikova for critically reading the manuscript and for assistance with the figures. This work was supported in part by grants from the Alzheimer's Association and the National Institutes of Health.

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DATABASES

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Alzheimer's disease

Down's syndrome

Inclusion body myositis

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Glossary

Declarative memory

Aspect of human memory that stores facts and experiences. It can be further subdivided into episodic memory and semantic memory.

Pathognomic

A lesion or sign, the occurrence of which provides evidence that a particular disease is present.

Multivesicular body

(MVB). MVBs have a role in transporting cargo to the lysosome system for degradation, and throughout the neuron for signalling purposes, and are important in regulating and degrading transmembrane proteins.

Neoepitope

Antibody recognition site of a terminal sequence in which the same sequence of amino acids are not recognized when located internally as part of the intact protein.

Mild cognitive impairment

(MCI). A transition stage between the cognitive changes of normal aging and Alzheimer's disease.

Retromer recycling endosomes

The retromer complex has been shown to be important in recycling transmembrane receptors from endosomes to the trans-Golgi network.

Holoprotein

The full-length, native polypeptide, before proteolytic cleavage events that might occur during maturation.

Minigene

A fragment of a genomic sequence that includes the exons and introns and is cloned into a eukaryotic expression vector.

Lipid raft

A specialized membrane domain that is enriched in cholesterol.

Nucleation seed

A molecule that facilitates the assembly of a polymeric structure.

Synaptosome

Isolated synapse of a neuron obtained via homogenization of nerve tissue.

Ubiquitin–proteasome system

Proteasomes are large protein complexes that degrade damaged or superfluous proteins that are tagged by a small protein called ubiquitin.

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LaFerla, F., Green, K. & Oddo, S. Intracellular amyloid-β in Alzheimer's disease. Nat Rev Neurosci 8, 499–509 (2007). https://doi.org/10.1038/nrn2168

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