Human tau increases amyloid β plaque size but not amyloid β-mediated synapse loss in a novel mouse model of Alzheimer's disease.

Alzheimer's disease is characterized by the presence of aggregates of amyloid beta (Aβ) in senile plaques and tau in neurofibrillary tangles, as well as marked neuron and synapse loss. Of these pathological changes, synapse loss correlates most strongly with cognitive decline. Synapse loss occurs prominently around plaques due to accumulations of oligomeric Aβ. Recent evidence suggests that tau may also play a role in synapse loss but the interactions of Aβ and tau in synapse loss remain to be determined. In this study, we generated a novel transgenic mouse line, the APP/PS1/rTg21221 line, by crossing APP/PS1 mice, which develop Aβ-plaques and synapse loss, with rTg21221 mice, which overexpress wild-type human tau. When compared to the APP/PS1 mice without human tau, the cross-sectional area of ThioS+ dense core plaques was increased by ~50%. Along with increased plaque size, we observed an increase in plaque-associated dystrophic neurites containing misfolded tau, but there was no exacerbation of neurite curvature or local neuron loss around plaques. Array tomography analysis similarly revealed no worsening of synapse loss around plaques, and no change in the accumulation of Aβ at synapses. Together, these results indicate that adding human wild-type tau exacerbates plaque pathology and neurite deformation but does not exacerbate plaque-associated synapse loss.

Jackson RJ ，Rudinskiy N ，Herrmann AG ，Croft S ，Kim JM ，Petrova V ，Ramos-Rodriguez JJ ，Pitstick R ，Wegmann S ，Garcia-Alloza M ，Carlson GA ，Hyman BT ，Spires-Jones TL ... -  《-》

The effect of focal brain injury on beta-amyloid plaque deposition, inflammation and synapses in the APP/PS1 mouse model of Alzheimer's disease.

Traumatic brain injury is a risk factor for Alzheimer's disease (AD), however the effect of such neural damage on the onset and progression of beta-amyloid (Aβ) plaque pathology is not well understood. This study utilized an in vivo model of focal brain injury to examine how localized damage may acutely affect the onset and progression of Aβ plaque deposition as well as inflammatory and synaptic changes, in the APP/PS1 (APPSWE, PSEN1dE9) transgenic model of AD relative to wild-type (Wt) mice. Acute focal brain injury in 3- and 9-month-old APP/PS1 and Wt mice was induced by insertion of a needle into the somatosensory neocortex, as compared to sham surgery, and examined at 24h and 7d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Aβ antibody) MOAB-2-labeled plaques at either 24h or 7d PI in 3-month-old APP/PS1 mice or Wt mice. Nine-month-old APP/PS1 mice demonstrate cortical Aβ plaques but focal injury had no statistically significant (p>0.05) effect on thioflavine-S or MOAB-2 plaque load surrounding the injury site at 24h PI or 7d PI. There was a significant (p<0.001) increase in cross-sectional cortical area occupied by Iba-1 positive microglia in injured mice compared to sham animals, however this response did not differ between APP/PS1 and Wt mice (p>0.05). For both Wt and APP/PS1 mice alike, synaptophysin puncta near the injury site were significantly reduced 24h PI (compared to sites distant to the injury and the corresponding area in sham mice; p<0.01), but not after 7d PI (p>0.05). There was no significant effect of genotype on this response (p>0.05). These results indicate that focal brain injury and the associated microglial response do not acutely alter Aβ plaque deposition in the APP/PS1 mouse model. Furthermore the current study demonstrated that the brains of both Wt and APP/PS1 mice are capable of recovering lost synaptophysin immunoreactivity post-injury, the latter in the presence of Aβ plaque pathology that causes synaptic degeneration.

Collins JM ，King AE ，Woodhouse A ，Kirkcaldie MT ，Vickers JC ... -  《-》

Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice.

Chen Y ，Zhao S ，Fan Z ，Li Z ，Zhu Y ，Shen T ，Li K ，Yan Y ，Tian J ，Liu Z ，Zhang B ... -  《Alzheimers Research & Therapy》

Alzheimer's disease pathological lesions activate the spleen tyrosine kinase.

Schweig JE ，Yao H ，Beaulieu-Abdelahad D ，Ait-Ghezala G ，Mouzon B ，Crawford F ，Mullan M ，Paris D ... -  《Acta Neuropathologica Communications》

Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer's disease mutants of APP and presenilin-1.

Boutajangout A ，Authelet M ，Blanchard V ，Touchet N ，Tremp G ，Pradier L ，Brion JP ... -  《NEUROBIOLOGY OF DISEASE》