Tau phosphorylation‐associated spine regression does not impair hippocampal‐dependent memory in hibernating golden hamsters

Abstract

The microtubule-associated protein tau, in its hyperphosphorylated form, is the major component of paired helical filaments and other aggregates in neurodegenerative disorders commonly referred to as "tauopathies". Recent evidence, however, indicates that mislocalization of hyperphosphorylated tau to subsynaptic sites leads to synaptic impairment and cognitive decline even long before formation of tau aggregates and neurodegeneration occur. A similar, but reversible hyperphosphorylation of tau occurs under physiologically controlled conditions during hibernation. Here, we study the hibernating Golden hamster (Syrian hamster, Mesocricetus auratus). A transient spine reduction was observed in the hippocampus, especially on apical dendrites of hippocampal CA3 pyramidal cells, but not on their basal dendrites. This distribution of structural synaptic regression was correlated to the distribution of phosphorylated tau, which was highly abundant in apical dendrites but hardly detectable in basal dendrites. Surprisingly, hippocampal memory assessed by a labyrinth maze was not affected by hibernation. The present study suggests a role for soluble hyperphosphorylated tau in the process of reversible synaptic regression, which does not lead to memory impairment during hibernation. We hypothesize that tau phosphorylation associated spine regression might mainly affect unstable/dynamic spines while sparing established/stable spines.

Glucocorticoid-mediated activation of GSK3β promotes tau phosphorylation and impairs memory in type 2 diabetes

“…Consistent with this interpretation, widespread and reversible phosphorylation of tau occurs in hibernating mammals (Arendt et al, 2003). Deficits in hippocampal function are dissociable from hypothermia-induced tau phosphorylation, as hibernating mammals awakened from torpor exhibit intact learning and memory despite widespread hippocampal tau phosphorylation (Bullman et al, 2016). Anesthesia-induced hypothermia also promotes hippocampal tau phosphorylation in normal mice (Planel et al, 2007b), but hippocampal long-term potentiation persists in anesthetized rodents despite a drop in core body temperature (Pavlides et al, 2002), and LTP magnitude is independent of brain temperature in awake rodents (Davis et al, 2004).…”

The Exceptional Vulnerability of Humans to Alzheimer’s Disease

“…Potentially relevant to species-specific differences in tauopathy is the hyperphosphorylation of tau in hibernating animals [48], a reversible state with few obvious aftereffects when animals return to euthermia [93]. Hamsters that hibernate do not exhibit plaques or tangles in old age [94], although aged bears can develop a tauopathy consisting of straight tau filaments [85].…”

Protein phosphatase 2A and tau: an orchestrated ‘Pas de Deux’

“…Increased phosphorylated tau levels coincide with downregulation of brain PP2A methylation and activity in hibernating Arctic ground squirrels . In hibernating golden hamsters, soluble hyperphosphorylated tau is associated with spine regression of hippocampal apical dendrites, but does not lead to memory impairment . In this context, the physiological purpose of increased tau phosphorylation, especially at the AD‐like PHF‐1 epitope, remains unclear.…”