Reducing Endogenous α-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model

J Neurosci. 2016 Jul 27;36(30):7971-84. doi: 10.1523/JNEUROSCI.0775-16.2016.

Abstract

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid β (Aβ) and microtubule associate protein tau, leading to the selective degeneration of neurons in the neocortex, limbic system, and nucleus basalis, among others. Recent studies have shown that α-synuclein (α-syn) also accumulates in the brains of patients with AD and interacts with Aβ and tau, forming toxic hetero-oligomers. Although the involvement of α-syn has been investigated extensively in Lewy body disease, less is known about the role of this synaptic protein in AD. Here, we found that reducing endogenous α-syn in an APP transgenic mouse model of AD prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. Together, these results suggest that α-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing α-syn might be a potential approach to protecting these populations from the toxic effects of Aβ.

Significance statement: Reducing endogenous α-synuclein (α-syn) in an APP transgenic mouse model of Alzheimer's disease (AD) prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. These results suggest that α-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing α-syn might be a potential approach to protecting these populations from the toxic effects of amyloid β.

Keywords: Alzheimer's disease; amyloid β oligomer; cholinergic neuron; selective vulnerability; transgenic animal model; α-synuclein.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Down-Regulation / genetics
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neurons / metabolism*
  • Neurons / pathology*
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*
  • rab3A GTP-Binding Protein / metabolism
  • rab5 GTP-Binding Proteins / metabolism

Substances

  • alpha-Synuclein
  • rab3A GTP-Binding Protein
  • rab5 GTP-Binding Proteins