Protective effects of synaptic stimulation against tauopathies
French Institute of Health and Medical Research | Inserm
Synapses are considered to be a primary target of pathology in Alzheimer's disease (AD) and other forms of dementia (Selkoe, 2002; Clare et al., 2010), and synapse loss has been considered the best correlate of memory impairment in AD (DeKosky and Scheff, 1990; Terry et al., 1991). Alterations of synaptic activity and reduced brain metabolism are among the earliest signs of AD pathology, which are detectable decades before the development of other symptoms (Reiman et al., 2004; Sperling et al., 2009). Therefore, the study of synaptic activity in AD has become an important subject for basic research as well as for the development of therapeutics. In the last fourteen years, multiple publications showed that synaptic activation affects amyloid precursor protein (APP) and Aβ homeostasis, and that it also protects synapses in models of AD Kamenetz et al., 2003; Cirrito et al., 2005; Tampellini et al., 2009; Tampellini and Gouras, 2010).
More recently, a limited number of studies was conducted to explore the effect of synaptic activity on tau homeostasis. It was shown that neuronal stimulation resulted in tau translocation to dendritic spines and increased tau secretion (Pooler et al., 2013; Frandemiche et al., 2014; Yamada et al., 2014); however, it is unclear whether, in a pathological context, these changes are positive or negative.
We provided evidence both in vivo and in vitro that synaptic activation is protective because it reduces levels of pathological tau, and it restores levels of synaptic proteins to normal, by stimulating the autophagic-lysosomal degradation pathway. On the contrary, inhibition of synaptic activity resulted in opposite outcomes, with buildup of tau oligomers in enlarged auto-lysosomes (Akwa et al., 2017). Our data indicate that synaptic activity counteracts the negative effects of pathological tau by acting on autophagy, providing a rationale for therapeutic use of synaptic stimulation in tauopathies.
Host: Estibaliz Capetillo