Induction of Tau Pathology by Intracerebral Infusion of Amyloid-β-Containing Brain Extract and by Amyloid-β Deposition in APP × Tau Transgenic Mice
Alzheimer's disease presents morphologically with senile plaques, primarily made of extracellular amyloid-β (Aβ) 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 Aβ-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 tau-depositing B6/P301L transgenic mice were infused. To further study Aβ-induced tau lesions B6/P301L tau transgenic mice were crossed with APP23 mice. Although Aβ deposition in double-transgenic mice did not differ from single APP23 transgenic mice, double-transgenic mice revealed increased tau pathology compared to single B6/P301L tau transgenic mice predominately in areas with high Aβ plaque load. The present results suggest that both extract-derived Aβ species and deposited fibrillary Aβ can induce the formation of tau neurofibrillary pathology. The observation that infused Aβ can trigger the tau pathology in the absence of Aβ deposits provides an explanation for the discrepancy between the neuroanatomical location of Aβ deposits and the development and spreading of tau lesions in Alzheimer's disease brain. Alzheimer's disease presents morphologically with senile plaques, primarily made of extracellular amyloid-β (Aβ) 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 Aβ-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 tau-depositing B6/P301L transgenic mice were infused. To further study Aβ-induced tau lesions B6/P301L tau transgenic mice were crossed with APP23 mice. Although Aβ deposition in double-transgenic mice did not differ from single APP23 transgenic mice, double-transgenic mice revealed increased tau pathology compared to single B6/P301L tau transgenic mice predominately in areas with high Aβ plaque load. The present results suggest that both extract-derived Aβ species and deposited fibrillary Aβ can induce the formation of tau neurofibrillary pathology. The observation that infused Aβ can trigger the tau pathology in the absence of Aβ deposits provides an explanation for the discrepancy between the neuroanatomical location of Aβ deposits and the development and spreading of tau lesions in Alzheimer's disease brain. Alzheimer's disease (AD) is a neurodegenerative disorder that is pathologically characterized by senile plaques, primarily composed of extracellular deposits of amyloid-β (Aβ) peptide, and neurofibrillary tangles, composed of intracellular aggregates of hyperphosphorylated tau protein.1Goedert M Spillantini MG A century of Alzheimer's disease.Science. 2006; 314: 777-781Crossref PubMed Scopus (1677) Google Scholar The amyloid cascade hypothesis of AD pathogenesis holds that accumulation of polymerized forms of Aβ 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.2Hardy J Selkoe DJ The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.Science. 2002; 297: 353-356Crossref PubMed Scopus (11263) Google Scholar Consistent with this view, previous in vivo studies have revealed an interaction between Aβ and tau pathology in vulnerable brain regions.3Lewis J Dickson DW Lin WL Chisholm L Corral A Jones G Yen SH Sahara N Skipper L Yager D Eckman C Hardy J Hutton M McGowan E Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.Science. 2001; 293: 1487-1491Crossref PubMed Scopus (1295) Google Scholar, 4Götz J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar, 5Oddo S Billings L Kesslak JP Cribbs DH LaFerla FM Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome.Neuron. 2004; 43: 321-332Abstract Full Text Full Text PDF PubMed Scopus (739) Google Scholar Previously we have shown that intracerebral injection of dilute Aβ-containing human and murine brain extracts induces cerebral amyloidosis in young, predepositing amyloid precursor protein (APP23) transgenic mice.6Meyer-Luehmann M Coomaraswamy J Bolmont T Kaeser S Schaefer C Kilger E Neuenschwander A Abramowski D Frey P Jaton AL Vigouret JM Paganetti P Walsh DM Mathews PM Ghiso J Staufenbiel M Walker LC Jucker M Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (802) Google Scholar In the present study we examined whether the same Aβ-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 Aβ was intracerebrally infused in tau transgenic mice.4Götz J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar However, in contrast to this latter study in which a high concentration of fibrillary synthetic Aβ was injected and gave rise to amyloid deposits in the host at the injection site, the Aβ in the brain extract was at low concentration and did not form amyloid deposits in the injected host.6Meyer-Luehmann M Coomaraswamy J Bolmont T Kaeser S Schaefer C Kilger E Neuenschwander A Abramowski D Frey P Jaton AL Vigouret JM Paganetti P Walsh DM Mathews PM Ghiso J Staufenbiel M Walker LC Jucker M Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (802) Google Scholar To complement this exogenous induction of tau pathology, we also crossbred B6/P301L tau transgenic mice with APP23 transgenic mice to study the induction of tau pathology by (genetic) expression of APP/Aβ. A similar cross breeding strategy has previously been reported to induce tau pathology in selected brain regions.3Lewis J Dickson DW Lin WL Chisholm L Corral A Jones G Yen SH Sahara N Skipper L Yager D Eckman C Hardy J Hutton M McGowan E Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.Science. 2001; 293: 1487-1491Crossref PubMed Scopus (1295) Google Scholar Our results suggest that both the infusion of an Aβ-containing extract and the deposition of fibrillary Aβ can induce the formation of neurofibrillary pathology. Heterozygous B6/P301L transgenic mice and nontransgenic wild-type littermate controls were used. B6/P301L mice were obtained by backcrossing the original P301L transgenic mice (JNPL3 mice)7Lewis J McGowan E Rockwood J Melrose H Nacharaju P Van Slegtenhorst M Gwinn-Hardy K Paul Murphy M Baker M Yu X Duff K Hardy J Corral A Lin WL Yen SH Dickson DW Davies P Hutton M Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.Nat Genet. 2000; 25: 402-405Crossref PubMed Scopus (1160) Google Scholar with C57BL/6J mice for at least seven generations. JNPL3 mice express the shortest four-repeat (4R0N) tau with the P301L mutation under control of the mouse prion promoter. B6/P301L transgenic mice were also crossbred with APP23 transgenic mice expressing human KM670/671NL mutant APP.8Sturchler-Pierrat C Abramowski D Duke M Wiederhold KH Mistl C Rothacher S Ledermann B Burki K Frey P Paganetti PA Waridel C Calhoun ME Jucker M Probst A Staufenbiel M Sommer B Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.Proc Natl Acad Sci USA. 1997; 94: 13287-13292Crossref PubMed Scopus (1265) Google Scholar Host mice were anesthetized with a mixture of ketamine (10 mg/kg body weight) and xylazine (20 mg/kg body weight) in saline. Unilateral stereotaxic injections of 2.5 μl of brain extracts were placed with a 5-μl Hamilton syringe into the right neocortex (A/P, −2.5 mm from bregma; L, −2.0 mm; D/V, −0.8 mm) and hippocampus (A/P, −2.5 mm from bregma; L, −2.0 mm; D/V, −1.8 mm). Injection speed was 1.25 and the was in for an was The was with and the was were in for of No was or after the were in with by the and extracts were by the neocortex of a APP23 transgenic mouse and an aged nontransgenic littermate extract was also from the and of a B6/P301L transgenic mouse were and at The were at in for and at for as previously M Coomaraswamy J Bolmont T Kaeser S Schaefer C Kilger E Neuenschwander A Abramowski D Frey P Jaton AL Vigouret JM Paganetti P Walsh DM Mathews PM Ghiso J Staufenbiel M Walker LC Jucker M Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (802) Google Scholar The was and To Aβ in the brain P M E S Abramowski D C Burki K van Staufenbiel M Mathews PM Jucker M Abeta is to the in a mouse of cerebral with 2004; PubMed Scopus Google Scholar were to in were to J A B G Staufenbiel M G E J and of and 1997; PubMed Scopus Google Scholar and were as were a and with to human Aβ The was were and To tau in the brain were in and on were a and with to of tau and The was were and Host mice were and were with in and for were on areas of to L Calhoun M F Wiederhold KH Walker L Staufenbiel M Jucker M and in the neocortex of amyloid precursor protein transgenic 2002; PubMed Google Scholar The were to tau at and of or of to and to were obtained from for In were with by the F of Alzheimer's neurofibrillary by of Acad Sci Google Scholar of sites for the of in the brain regions of were L of the of in the of the hippocampus the PubMed Scopus Google Scholar the hippocampus mm to mm from entorhinal cortex −2.5 mm to cortex mm to mm to and mm to mm) was with to the to the entorhinal to seven the cortex and amygdala, and to the brain were The brain regions were at low to G The in Scholar a single a was to for of were with an a with a to a To the for (20 to brain were to by with of the by was the of and with the of To the of Aβ deposition in we have the same as for the of the hippocampus mm to mm from neocortex mm to mm to and brain mm to mm) was with to the hippocampus and to the amygdala, and to the brain were a were with a and to for the by of and with the of a P301L transgenic mice tau pathology between to months of disease in is between and J Dickson DW Lin WL Chisholm L Corral A Jones G Yen SH Sahara N Skipper L Yager D Eckman C Hardy J Hutton M McGowan E Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.Science. 2001; 293: 1487-1491Crossref PubMed Scopus (1295) Google Scholar, J McGowan E Rockwood J Melrose H Nacharaju P Van Slegtenhorst M Gwinn-Hardy K Paul Murphy M Baker M Yu X Duff K Hardy J Corral A Lin WL Yen SH Dickson DW Davies P Hutton M Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.Nat Genet. 2000; 25: 402-405Crossref PubMed Scopus (1160) Google Scholar To and to in brain extract infusion studies and P301L transgenic mice were to a C57BL/6J for at least seven B6/P301L and B6/P301L mice revealed a in the development of tau pathology compared to the original P301L mice. In B6/P301L mice intracellular tau deposition with was not in a of to mice is the months of B6/P301L mice and were to when by the to months of disease mice and were of that of mice was and similar to the original of P301L mice on the J McGowan E Rockwood J Melrose H Nacharaju P Van Slegtenhorst M Gwinn-Hardy K Paul Murphy M Baker M Yu X Duff K Hardy J Corral A Lin WL Yen SH Dickson DW Davies P Hutton M Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.Nat Genet. 2000; 25: 402-405Crossref PubMed Scopus (1160) Google Scholar a of hyperphosphorylated tau protein in of the brain and also of the entorhinal and In the and brain and the to of tau lesions were similar to neurofibrillary tangles in AD brain. were by degeneration in of the and by in similar as previously in P301L mice on a J McGowan E Rockwood J Melrose H Nacharaju P Van Slegtenhorst M Gwinn-Hardy K Paul Murphy M Baker M Yu X Duff K Hardy J Corral A Lin WL Yen SH Dickson DW Davies P Hutton M Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.Nat Genet. 2000; 25: 402-405Crossref PubMed Scopus (1160) Google Scholar B6/P301L mice did not to months of a of B6/P301L mice revealed only tau pathology in the and with of tau lesions in areas of the brain. were from the neocortex of Aβ-depositing APP23 mice and an nontransgenic control littermate A and of the APP23 brain extract revealed Aβ of to with compared to with previous M Coomaraswamy J Bolmont T Kaeser S Schaefer C Kilger E Neuenschwander A Abramowski D Frey P Jaton AL Vigouret JM Paganetti P Walsh DM Mathews PM Ghiso J Staufenbiel M Walker LC Jucker M Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (802) Google Scholar, P M E S Abramowski D C Burki K van Staufenbiel M Mathews PM Jucker M Abeta is to the in a mouse of cerebral with 2004; PubMed Scopus Google Scholar an an extract from the brain and of an aged B6/P301L transgenic mouse was used. and the of tau lesions and of the shortest human tau was C and were injected into the right hippocampus and cortex of young to B6/P301L mice. mice were months when host mice were to months of that B6/P301L mice have not tau pathology injection of the APP23 extract induced deposition of tau the injected hippocampus by A and In contrast injection of nontransgenic brain extract or did not induce tau lesions C and tau pathology was also induced with the B6/P301L but this was not and APP23 extracts injected into nontransgenic mice did not induce tau deposits that the expression of human tau was for the induction of tau lesions by the Aβ-containing were by pathology induction in regions in B6/P301L tau mice. of by of extract in the hippocampus the induction of tau deposition by the APP23 extract compared to P is and compared to the induction also in brain regions from the injection site, such as the entorhinal cortex and the revealed induction of the APP23 extract compared to P and to the which for the also induction compared to D and No induced tau pathology was in the cortex and brain P extract from an aged APP23 mouse wild-type nontransgenic extract from an aged B6/P301L mouse No tau lesions were observed the injection of the pathology, was induced in brain regions from the injection such as the entorhinal cortex and the amygdala, but not brain and In regions tau induction to the injected However, in the the to a also to the injection for Aβ at after the infusion of the Aβ-containing extracts did not Aβ deposition not with previous M Coomaraswamy J Bolmont T Kaeser S Schaefer C Kilger E Neuenschwander A Abramowski D Frey P Jaton AL Vigouret JM Paganetti P Walsh DM Mathews PM Ghiso J Staufenbiel M Walker LC Jucker M Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (802) Google Scholar was to the and was similar mice of whether were injected with or brain B6/P301L tau transgenic mice were crossed with APP23 transgenic mice. amyloid double-transgenic B6/P301L APP23 mice did not increased tau pathology compared to the single transgenic B6/P301L littermate control mice not However, at the of amyloid a of tau pathology by in the entorhinal and to a in the but not in brain regions was in the double-transgenic B6/P301L APP23 mice compared to the single transgenic B6/P301L control mice. was for the double-transgenic mice months not and in double-transgenic mice months A and single B6/P301L tau mice not tau pathology to this In the entorhinal cortex and a of induced tau lesions were of the amyloid did not between B6/P301L APP23 and single transgenic APP23 mice. was a of amyloid deposition with neocortex and hippocampus the amyloid by the and the brain with the latter amyloid deposition lesions were induced in the of in the entorhinal cortex and hippocampus E and in the was a with induced tau lesions in the and amyloid deposition in the and In areas not to tau pathology in B6/P301L mice, such as the and was or only modest tau pathology induction in the double-transgenic mice a high plaque In mice amyloid deposits were by a of and similar to previous results in APP23 C Abramowski D Duke M Wiederhold KH Mistl C Rothacher S Ledermann B Burki K Frey P Paganetti PA Waridel C Calhoun ME Jucker M Probst A Staufenbiel M Sommer B Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.Proc Natl Acad Sci USA. 1997; 94: 13287-13292Crossref PubMed Scopus (1265) Google Scholar, M A Probst A Sommer B Staufenbiel M Jucker M of with amyloid in of APP23 transgenic J Full Text Full Text PDF PubMed Scopus Google Scholar The present study was to confirm and expand previous in vivo studies a between Aβ and the induction of neurofibrillary J Dickson DW Lin WL Chisholm L Corral A Jones G Yen SH Sahara N Skipper L Yager D Eckman C Hardy J Hutton M McGowan E Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.Science. 2001; 293: 1487-1491Crossref PubMed Scopus (1295) Google Scholar, 4Götz J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar have shown that tau pathology can induced in the brain of young B6/P301L tau transgenic mice by a single injection of a dilute Aβ-containing extract of a transgenic APP23 mouse but not by nontransgenic control or extract from a transgenic B6/P301L mouse brain with tau suggest that Aβ is to an induction of the tau pathology. A similar induction of tau pathology, only in the amygdala, has been after the infusion of synthetic into the cortex and hippocampus of a tau transgenic mouse J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar However, between the studies and J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar injected fibrillary synthetic Aβ at a high concentration and the injected Aβ was as amyloid and at the injection In a dilute with a to Aβ concentration to was in the present and J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar as host a mouse with the same P301L that tau pathology to months of the B6/P301L mouse in the present the induction of tau lesions after the injection in the present study was months after and J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar reported that the induced tau lesions were the of the induced tau lesions in the present study were and of this by the in of neurofibrillary lesions of the transgenic or the concentration of the injected have previously shown that extracts to the APP23 extracts have synthetic Aβ did not similar M Coomaraswamy J Bolmont T Kaeser S Schaefer C Kilger E Neuenschwander A Abramowski D Frey P Jaton AL Vigouret JM Paganetti P Walsh DM Mathews PM Ghiso J Staufenbiel M Walker LC Jucker M Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (802) Google Scholar results we that the in brain a or of Aβ that is from synthetic from this latter study and the of and J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar a of the and tau of Aβ species synthetic Aβ is for the induction of the tau pathology but not for the induction of M Coomaraswamy J Bolmont T Kaeser S Schaefer C Kilger E Neuenschwander A Abramowski D Frey P Jaton AL Vigouret JM Paganetti P Walsh DM Mathews PM Ghiso J Staufenbiel M Walker LC Jucker M Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.Science. 2006; 313: 1781-1784Crossref PubMed Scopus (802) Google Scholar However, of the between the present study and that of and J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar the that synthetic Aβ and Aβ-containing brain extract of tau pathology to the hypothesis of a of the of Aβ from the of studies in which brain extract synthetic Aβ in the same transgenic The observation that tau lesions were induced not only at the injection site, but also in areas such as entorhinal cortex and amygdala, and at the sites by the of brain regions to the injection J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar, AL T M Calhoun ME M Sommer B Staufenbiel M Jucker M amyloid induces and formation in amyloid precursor protein transgenic PubMed Google Scholar Aβ species to with and to and C Selkoe DJ protein in from the Alzheimer's amyloid PubMed Scopus Google Scholar which in to and induction of tau lesions in the is also that Aβ is and to the Aβ with tau and induces tau and J A J induce tau and of Full Text PDF PubMed Scopus Google Scholar, LC F Exogenous induction of cerebral in 2002; PubMed Scopus Google Scholar, JP T J Abeta and tau form that of both into the forms observed in Alzheimer's Natl Acad Sci USA. 2006; PubMed Scopus Google Scholar of the the of with induced tau lesions at least induction of tau lesions was in the entorhinal cortex and but not in the brain which only projection to the injection The of induction of tau pathology in the cortex a of low of this to form tau lesions in such tau transgenic mice.4Götz J Chen F van Dorpe J Nitsch RM Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.Science. 2001; 293: 1491-1495Crossref PubMed Scopus (1299) Google Scholar, J McGowan E Rockwood J Melrose H Nacharaju P Van Slegtenhorst M Gwinn-Hardy K Paul Murphy M Baker M Yu X Duff K Hardy J Corral A Lin WL Yen SH Dickson DW Davies P Hutton M Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.Nat Genet. 2000; 25: 402-405Crossref PubMed Scopus (1160) Google Scholar, B E M K H M M C A B Spillantini MG M tau and in transgenic mice expressing human tau 2002; PubMed Google Scholar In or to such a of tau pathology the infused Aβ have been via via to the and M Paul DM In vivo of brain with in and PubMed Google Scholar, of Alzheimer's Full Text Full Text PDF PubMed Scopus Google Scholar pathology was also induced in B6/P301L transgenic mice when crossed with APP23 mice, a previous study in which the same tau transgenic mouse on a was crossed with transgenic J Dickson DW Lin WL Chisholm L Corral A Jones G Yen SH Sahara N Skipper L Yager D Eckman C Hardy J Hutton M McGowan E Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.Science. 2001; 293: 1487-1491Crossref PubMed Scopus (1295) Google Scholar Although in the infusion Aβ species have the tau pathology, in the B6/P301L APP23 transgenic mice, that the tau lesions were by an interaction of tau and both the of the APP23 and of the B6/P301L to a in similar neuronal J M T J A for expressing in the and of transgenic PubMed Scopus Google Scholar, ME P AL M M Wiederhold KH Abramowski D C Sommer B Staufenbiel M Jucker M of mutant amyloid precursor protein results in deposition of Natl Acad Sci USA. PubMed Scopus Google Scholar However, the induction of the tau lesions with the of cerebral is that the extracellular deposition of amyloid is the trigger of the neurofibrillary pathology. The of a induction of the tau pathology by the amyloid deposits is by the of tau pathology induction amyloid load. The induction of tau pathology was in the entorhinal by amygdala, and brain we the plaque in the entorhinal by the the amygdala, and brain However, with previous J Dickson DW Lin WL Chisholm L Corral A Jones G Yen SH Sahara N Skipper L Yager D Eckman C Hardy J Hutton M McGowan E Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.Science. 2001; 293: 1487-1491Crossref PubMed Scopus (1295) Google Scholar neurofibrillary were not in of the amyloid deposits in the amygdala, with a induction of tau pathology but amyloid suggest that in the double-transgenic mice tau induction in areas amyloid aggregates from areas with amyloid deposits similar to the with the Aβ-containing brain Although the infusion Aβ species as the trigger of the induced tau pathology in the of tau induction in the crossed mice is for amyloid deposition is by a M A Probst A Sommer B Staufenbiel M Jucker M of with amyloid in of APP23 transgenic J Full Text Full Text PDF PubMed Scopus Google Scholar, H S S B J P M S H M G L J G C J Van Walker D S B G T and Alzheimer's 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, F L T Coomaraswamy J Staufenbiel M Jucker M of into the brain of amyloid precursor protein transgenic 25: PubMed Scopus Google Scholar and has been to the of tau pathology in transgenic M B N J T and tangles in a mouse Full Text Full Text PDF PubMed Scopus Google Scholar has also been shown that induce and AL T M Calhoun ME M Sommer B Staufenbiel M Jucker M amyloid induces and formation in amyloid precursor protein transgenic PubMed Google Scholar, J J Duff K amyloid deposition leads to and of neuronal 2004; PubMed Scopus Google Scholar which in tau In results suggest that Aβ can induce neurofibrillary pathology by In the observation that infused Aβ can trigger the tau pathology in the absence of amyloid deposits provides an explanation for the discrepancy between the neuroanatomical location of amyloid deposits, or absence and the development and spreading of tau lesions in AD brain. Calhoun for and Paganetti and Walsh for the of