Induction of Tau Pathology by Intracerebral Infusion of Amyloid-β-Containing Brain Extract and by Amyloid-β Deposition in APP × Tau Transgenic Mice

Abstract

Alzheimer's disease presents morphologically with senile plaques, primarily made of extracellular amyloid-␤ (A␤) deposits, and neurofibrillary lesions, which consist of intracellular aggregates of hyperphosphorylated tau protein. To study the in vivo induction of tau pathology, dilute brain extracts from aged A␤-depositing APP23 transgenic mice were intracerebrally infused in young B6/P301L tau transgenic mice. Six months after the infusion, tau pathology was induced in the injected hippocampus but also in brain regions well beyond the injection sites such as the entorhinal cortex and amygdala, areas with neuronal projection to the injection site. No or only modest tau induction was observed when brain extracts from aged nontransgenic control mice and aged taudepositing B6/P301L transgenic mice were infused. Alzheimer's disease (AD) is a neurodegenerative disorder that is pathologically characterized by senile plaques, primarily composed of extracellular deposits of amyloid-␤ (A␤) peptide, and neurofibrillary tangles, composed of intracellular aggregates of hyperphosphorylated tau protein. 1The amyloid cascade hypothesis of AD pathogenesis holds that accumulation of polymerized forms of A␤ in the brain is an early and critical event that triggers a cascade of events leading to hyperphosphorylation and somatodendritic segregation of tau and formation of neurofibrillary tangles. 2Consistent with this view, previous in vivo studies have revealed an interaction between A␤ and tau pathology in vulnerable brain regions. 3-5Previously we have shown that intracerebral injection of dilute A␤-containing human and murine brain extracts induces cerebral amyloidosis in young, predepositing amyloid precursor protein (APP23) transgenic mice. 6 In the present study we examined whether the same A␤-containing brain extracts would also induce tau pathology in young B6/P301L mutated tau transgenic mice and thus confirm and expand previous studies in which synthetic A␤ was intracerebrally infused in tau transgenic mice. 4 However, in contrast to this latter study in which a high concentration of fibrillary synthetic A␤ was injected

Brain homogenates from human tauopathies induce tau inclusions in mouse brain

“…The amyloid cascade hypothesis of AD pathogenesis posits that the aggregation of Aβ triggers the formation of tau inclusions (39). Consistent with this view, previous work has demonstrated an interaction between Aβ and tau pathologies in some brain regions (40)(41)(42)(43)(44). However, in these studies, both APP and tau were mutant, unlike what is the case in AD, where tau is wild type (1).…”

“…Western blotting for tau was done as described (20) using HT7, an antibody specific for human tau (1:1,000; Pierce), AT8 (1:1,000) and AT100 (1:200). Western blotting for Aβ was carried out as described (43) using the human-specific monoclonal antibody 1E8 (1:1,000; Signet).…”

Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity

“…The frontal cortex section of the human brain was selected because it contains high amounts of Aβ aggregates (1, 2). First, we examined reactivity of L2-a and L2-b with the supernatants of homogenized human AD brain tissue samples, prepared following the method previously established (53). The metal contents (Cu and Zn) of the supernatants of the human brain homogenates were determined by inductively coupled plasma mass spectrometry (ICP-MS).…”

Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF ‐like conformation of Tau protein

“…Aβ1‐42 polymerization is believed to occur in sequential phases: First Aβ monomers aggregate into soluble oligomers that then form insoluble oligomers, generating protofibrils and fibrils (Hubin et al ., 2014). Soluble Aβ1‐42 oligomers constitute the more toxic form of the peptide (Bolmont et al ., 2007; Nimmrich & Ebert, 2009; Guglielmotto et al ., 2014). Monomers have been proposed to be involved, preferentially, in physiologic processes (Puzzo et al ., 2011; Piccini et al ., 2012).…”

“…How Aβ mediates alteration and aggregation of Tau is uncertain, although three major mechanisms have been proposed: (i) Aβ activates kinases that phosphorylate Tau (Hernández & Avila, 2010; Llorens‐Martín et al ., 2014) altering its capacity to bind tubulin; (ii) Aβ alters the proteasomal degradation of Tau, increasing its concentration in free state (Oddo et al ., 2009); (iii) Aβ intracellular aggregates have a nucleation effect on Tau (Guo et al ., 2006; Bolmont et al ., 2007). The third hypothesis is supported by the occurrence of Tau pathology in different types of cerebral amyloidosis (Holton et al ., 2001; Giaccone et al ., 2008).…”