Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimer's disease

Abstract

Tau alterations are now considered an executor of neuronal demise and cognitive dysfunction in Alzheimer's disease (AD). Mouse models combining amyloidosis and tauopathy and their parental counterparts are important tools to further investigate the interplay of abnormal amyloid-β (Aβ) and Tau species in pathogenesis, synaptic and neuronal dysfunction, and cognitive decline. Here, we crossed APP/PS1 mice with 5 early-onset familial AD mutations (5xFAD) and TauP301S (PS19) transgenic mice, denoted F(+)/T(+) mice, and phenotypically compared them to their respective parental strains, denoted F(+)/T(-) and F(-)/T(+) respectively, as controls. We found dramatically aggravated tauopathy (~10-fold) in F(+)/T(+) mice compared to the parental F(-)/T(+) mice. In contrast, amyloidosis was unaltered compared to the parental F(+)/T(-) mice. Tauopathy was invariably and very robustly aggravated in hippocampal and cortical brain regions. Most important, F(+)/T(+) displayed aggravated cognitive deficits in a hippocampus-dependent spatial navigation task, compared to the parental F(+)/T(-) strain, while parental F(-)/T(+) mice did not display cognitive impairment. Basal synaptic transmission was impaired in F(+)/T(+) mice compared to nontransgenic mice and the parental strains (≥40%). Finally, F(+)/T(+) mice displayed a significant hippocampal atrophy (~20%) compared to nontransgenic mice, in contrast to the parental strains. Our data indicate for the first time that pathological Aβ species (or APP/PS1) induced changes in Tau contribute to cognitive deficits correlating with synaptic deficits and hippocampal atrophy in an AD model. Our data lend support to the amyloid cascade hypothesis with a role of pathological Aβ species as initiator and pathological Tau species as executor.

Retroviral induction of GSK-3β expression blocks the stimulatory action of physical exercise on the maturation of newborn neurons

“…It is considered that one of the most important downstream effectors of GSK-3b activity is the microtubule-associated protein Tau [45]. Tau phosphorylation by GSK-3b is thought to be responsible for the memory impairment found in AD [46]. At the molecular level, GSK-3b has a deleterious effect on neuron connectivity and it has been implicated in the internalization of AMPA receptors.…”

The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease

“…Although the degree of tauopathy correlates more strongly with cognitive decline than does the buildup of Ab (Giannakopoulos et al 2003), extant evidence indicates that in AD (Hardy and Selkoe 2002;Holtzman et al 2011;Nelson et al 2012) and in genetically modified mice (Götz et al 2001;Lewis et al 2001;Bolmont et al 2007;Héraud et al 2014;Stancu et al 2014;Vasconcelos et al 2016), tauopathy is downstream from Ab proteopathy. Moreover, the genetic causes of autosomal dominant AD identified so far all affect Ab by enhancing its release from the Ab-precursor protein (APP) or its tendency to self-aggregate (Hardyand Selkoe 2002).…”

Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation

“…Aβ induces tau phosphorylation, enhances tau pathology, and accelerates NFT formation [10][11][12][13][14][15]. Tau is phosphorylated by a variety of serine/threonine protein kinases such as GSK-3β, cyclin-dependent kinase 5 (CDK5), extracellular-signalregulated kinase 2 (ERK2), S6 kinase, microtubule-affinityregulating kinase (MARK), SAD kinase, and PKA or Src family kinases such as fyn and c-Abl [16][17][18].…”