Hebbian plasticity: The elusive missing link at the heart of Alzheimer’s disease pathogenesis?

Abstract

The amyloid cascade hypothesis of Alzheimer’s pathogenesis: The amyloid cascade hypothesis of Alzheimer’s disease (AD) pathogenesis will shortly celebrate its thirtieth birthday (Hardy and Higgins, 1992). Based on abundant genetic and biochemical evidence, it proposes that deposition of the amyloid-β (Aβ) peptide in brain parenchyma is an essential upstream trigger in AD pathogenesis that drives a cascade of events, specifically including the recruitment and pathological hyper-phosphorylation of the micro-tubule-associated protein tau, that culminate in derangement of synaptic function and, eventually, neuronal death. Although the hypothesis has been challenged many times over the last three decades, principally based on a number of observations of AD pathology and clinical progression that it appears not to readily explain (Makin, 2018), its fundamental assertions that Aβ deposition is a critical early event, and that this somehow leads to the later recruitment of hyperphosphorylated tau, still appear to hold true (Selkoe and Hardy, 2016). Therefore, and in spite of its difficulties, the amyloid cascade hypothesis, albeit slightly refined and qualified over the years, is still the dominant model of AD pathogenesis. The central importance of tau to the disease process has been confirmed by a number of more recent studies that demonstrate convincingly that tau is essential for many of the canonical AD-associated synaptic and behavioral phenotypes, which can be rescued in animal models of AD by tau knockout (Mucke and Selkoe, 2012). However, despite its clear significance in AD pathogenesis, the cellular mechanism by which Aβ recruits tau to bring about synaptic and cognitive decline has remained obscure. Dysfunctional Hebbian plasticity links Aβ to tau in a model of AD: One of the most important and best-studied AD-related phenotypes associated with exposure to pathogenic forms of Aβ, in particular the oligomeric forms of Aβ (Aβo) that are particularly potent in pathogenesis, is the modulation of Hebbian synaptic plasticity processes. These changes have been best studied at the CA3-CA1 (Schaffer collateral) synapse in the hippocampus, where exposure to Aβo causes a loss of synaptic long-term potentiation and facilitation or enhancement of long-term depression (LTD). We were initially intrigued by the finding that these effects are mediated via an extra-synaptic population of postsynaptic N-methyl-D-aspartic acid (NMDA)-type glutamate receptors (Mucke and Selkoe, 2012), because extra-synaptic NMDA receptors are particularly efficiently activated at synapses with a high probability of release (Pr) (Lozovaya et al., 1999), an index of how efficiently action potentials are converted to neurotransmitter release events at the presynaptic terminal. Several studies have reported increases in Pr following exposure to Aβo (Taylor et al., 2021) and we, therefore, formulated a hypothesis that in the context of AD, enhancements in neurotransmitter release probability might drives greater activation of extra-synaptic glutamate receptors and consequently changes in Hebbian plasticity, specifically the enhancement of LTD. A pointer towards a potential link between altered plasticity and tau came with a more recent study that demonstrated that under physiological conditions, the induction of LTD recruits and phosphorylates tau, albeit at just two sites (Regan et al., 2015). Accordingly, we extended our hypothesis to suggest that the enhanced LTD seen following Aβo exposure might similarly recruit and phosphorylate tau, but perhaps to an even greater degree than seen during normal LTD. To test our hypothesis, we began by examining the action potential-evoked release of previously loaded fluorescent FM dyes from presynaptic terminals of hippocampal CA3-CA1 synapses in rodent organotypic hippocampal slices. These experiments showed faster dye unloading following treatment with Aβo, confirming increased Pr (Taylor et al., 2021), and we then turned to acute hippocampal slices to show that Aβo also drive an enhancement in the magnitude of CA3-CA1 LTD induced by low-frequency synaptic stimulation, which has been previously reported. However, we also showed that normalization of probability of release by partial inhibition of presynaptic voltage-gated Ca2+ channels can rescue the enhanced LTD, restoring it to a normal level. We then wished to study the link between Aβo-enhanced LTD and tau phosphorylation. As these next experiments involved more chronic Aβo exposure, we returned to using organotypic slices to firstly show that tau hyperphosphorylation, which we assessed using an antibody recognizing phosphorylation at specific pathologically-relevant tau residues, was enhanced following Aβo treatment, and that this also could be rescued by either partial blockade of presynaptic Ca channels to normalize Pr, or by blockade of the NMDA receptors that are responsible for LTD induction. While together, these results suggest that Aβ-media