Improved Long-Term Potentiation and Memory in Young Tau-P301L Transgenic Mice before Onset of Hyperphosphorylation and Tauopathy

Abstract

The microtubule binding protein tau is implicated in neurodegenerative tauopathies, including frontotemporal dementia (FTD) with Parkinsonism caused by diverse mutations in the tau gene. Hyperphosphorylation of tau is considered crucial in the age-related formation of neurofibrillary tangles (NFTs) correlating well with neurotoxicity and cognitive defects. Transgenic mice expressing FTD mutant tau-P301L recapitulate the human pathology with progressive neuronal impairment and accumulation of NFT. Here, we studied tau-P301L mice for parameters of learning and memory at a young age, before hyperphosphorylation and tauopathy were apparent. Unexpectedly, in young tau-P301L mice, increased long-term potentiation in the dentate gyrus was observed in parallel with improved cognitive performance in object recognition tests. Neither tau phosphorylation, neurogenesis, nor other morphological parameters that were analyzed could account for these cognitive changes. The data demonstrate that learning and memory processes in the hippocampus of young tau-P301L mice are not impaired and actually improved in the absence of marked phosphorylation of human tau. We conclude that protein tau plays an important beneficial role in normal neuronal processes of hippocampal memory, and conversely, that not tau mutations per se, but the ensuing hyperphosphorylation must be critical for cognitive decline in tauopathies.

Corticosterone time-dependently modulates β-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus

“…As suggested by earlier reports, TBS can become effective in the dentate gyrus, when GABA A inhibitory activity is prevented (Alfarez et al 2003;Boekhoorn et al 2006). This was confirmed in the current study if the vehicle group was tested in the presence of 10 µM ‫-)מ(‬ bicuculline methiodide.…”

Glutamate Metabolism is Impaired in Transgenic Mice with Tau Hyperphosphorylation

“…The apparent metabolic dysfunction as a consequence of tau pathology lends support to the hypothesis that abnormally phosphorylated tau is detrimental for neuronal function. 34,35 Increased Turnover of Metabolites in Cortical Neurons and Astrocytes In contrast to the decrease in glucose utilization demonstrated in FTD patients, 14 the decreased concentration of [1-13 C]glucose in cortex suggests that glucose utilization was increased in pR5 mice. 36 In addition, the almost universal increase in the 13 [4-13 C]glutamine in the present study is probably a result of both the increased turnover of glutamate in the neuronal compartment and increased turnover of glutamine in astrocytes.…”

“…At age 1 to 2 months, before the onset of marked tau hyperphosphorylation, other lines of mice that also express the P301L mutation display paradoxical increases in long-term potentiation of synapses in dentate gyrus and in dendritic spine maturation in addition to improved cognitive performance compared with controls. 34,40 The downregulation of several metabolism-related proteins and reduced complex I activity as measured in the whole brain at the ages 8.5 to 12 months suggests that metabolic dysfunction occurs in pR5 mice with increased aggregation of tau. However, mitochondrial respiration, ATP production, and oxidative status as measured in one hemisphere are preserved until advanced age and massive NFT deposition.…”

Is it Premature to assume that Prion-like Propagation of Protein Misfolding is the Universal Model of Lesion Spread in Neurodegeneration?

“…A fairly strong case can also be made for the involvement of prion-like mechanisms in the interneuronal transfer of neurotoxicity that involves non-PrP proteins in at least some circumstances. Common features of PrP and non-PrP disease proteins consistent with such a role include 1) a demonstrated toxicity mechanism linked to oligomerization [38], 2) an involvement with plasticity/memory associated synaptic functions [39,40] some of which may require long term conformational changes in specific proteins that appear to correlate with prion-like behavior [41][42][43], and 3) physical properties such as having multiple stable conformations and a chaperone-like ability to interact with other proteins and influence their conformations [44]. Recent cellular studies that suggest that templating might actually mediate toxicity or at least aggregate propagation [45,46].…”