Soluble Conformers of Aβ and Tau Alter Selective Proteins Governing Axonal Transport.

Despite the demonstration that amyloid-β (Aβ) can trigger increased tau phosphorylation and neurofibrillary tangle (NFT) formation in vivo, the molecular link associating Aβ and tau pathologies remains ill defined. Here, we observed that exposure of cultured primary neurons to Aβ trimers isolated from brain tissue of subjects with Alzheimer's disease led to a specific conformational change of tau detected by the antibody Alz50. A similar association was supported by postmortem human brain analyses. To study the role of Aβ trimers in vivo, we created a novel bigenic Tg-Aβ+Tau mouse line by crossing Tg2576 (Tg-Aβ) and rTg4510 (Tg-Tau) mice. Before neurodegeneration and amyloidosis, apparent Aβ trimers were increased by ∼2-fold in 3-month-old Tg-Aβ and Tg-Aβ+Tau mice compared with younger mice, whereas soluble monomeric Aβ levels were unchanged. Under these conditions, the expression of soluble Alz50-tau conformers rose by ∼2.2-fold in the forebrains of Tg-Aβ+Tau mice compared with nontransgenic littermates. In parallel, APP accumulated intracellularly, suggestive of a putative dysfunction of anterograde axonal transport. We found that the protein abundance of the kinesin-1 light chain (KLC1) was reduced selectively in vivo and in vitro when soluble Aβ trimers/Alz50-tau were present. Importantly, the reduction in KLC1 was prevented by the intraneuronal delivery of Alz50 antibodies. Collectively, our findings reveal that specific soluble conformers of Aβ and tau cooperatively disrupt axonal transport independently from plaques and tangles. Finally, these results suggest that not all endogenous Aβ oligomers trigger the same deleterious changes and that the role of each assembly should be considered separately. The mechanistic link between amyloid-β (Aβ) and tau, the two major proteins composing the neuropathological lesions detected in brain tissue of Alzheimer's disease subjects, remains unclear. Here, we report that the trimeric Aβ species induce a pathological modification of tau in cultured neurons and in bigenic mice expressing Aβ and human tau. This linkage was also observed in postmortem brain tissue from subjects with mild cognitive impairment, when Aβ trimers are abundant. Further, this modification of tau was associated with the intracellular accumulation of the precursor protein of Aβ, APP, as a result of the selective decrease in kinesin light chain 1 expression. Our findings suggest that Aβ trimers might cause axonal transport deficits in AD.

Sherman MA ，LaCroix M ，Amar F ，Larson ME ，Forster C ，Aguzzi A ，Bennett DA ，Ramsden M ，Lesné SE ... -  《-》

Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice.

Umeda T ，Maekawa S ，Kimura T ，Takashima A ，Tomiyama T ，Mori H ... -  《-》

Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein.

Gomes LA ，Hipp SA ，Rijal Upadhaya A ，Balakrishnan K ，Ospitalieri S ，Koper MJ ，Largo-Barrientos P ，Uytterhoeven V ，Reichwald J ，Rabe S ，Vandenberghe R ，von Arnim CAF ，Tousseyn T ，Feederle R ，Giudici C ，Willem M ，Staufenbiel M ，Thal DR ... -  《-》

Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice.

Hypercholesterolemia is known to be a risk factor for Alzheimer's disease (AD), and diet-induced hypercholesterolemia has been shown to accelerate amyloid pathology in animals. While growing evidence has shown that synaptic and cognitive dysfunction in AD is associated with intraneuronal accumulation of Aβ, the relationships between hypercholesterolemia, memory impairment, and intraneuronal Aβ remains unclear. The present study aims to clarify this association. Transgenic mice expressing amyloid precursor protein (APP) harboring the Osaka (E693∆) mutation (APP(OSK)-Tg mice) were used. These mice exhibit intraneuronal Aβ oligomers and memory impairment from 8months of age. Five-month-old male APP(OSK)-Tg mice and non-Tg littermates were fed a high-cholesterol diet for 1 month to induce hypercholesterolemia. At 6 months of age, their cognitive function was evaluated by the Morris water maze. Intraneuronal Aβ, synaptic density, and tau phosphorylation were examined by immunohistochemistry. Serum and brain cholesterol levels were significantly higher in APP(OSK)-Tg mice and non-Tg littermates that were fed a high-cholesterol diet than in control mice that were fed normal chow, indicating that hypercholesterolemia was successfully induced. Hypercholesterolemic APP(OSK)-Tg mice, but not control APP(OSK)-Tg mice or hypercholesterolemic non-Tg littermates, exhibited impaired spatial reference memory, which was accompanied with intraneuronal accumulation of Aβ oligomers, reduced synaptophysin immunoreactivity, and abnormal tau phosphorylation in the hippocampus. Hypercholesterolemia-accelerated accumulation of intraneuronal Aβ oligomers was also observed in another model mouse, Tg2576. Our findings suggest that hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers and subsequent synapse loss, resulting in memory impairment.

Umeda T ，Tomiyama T ，Kitajima E ，Idomoto T ，Nomura S ，Lambert MP ，Klein WL ，Mori H ... -  《-》

[Alzheimer disease: cellular and molecular aspects].

Octave JN 《-》