Tau and Amyloid β Protein in Patient-Derived Aqueous Brain Extracts Act Concomitantly to Disrupt Long-Term Potentiation in Vivo

Amyloid beta protein (A beta) and tau, the two main proteins implicated in causing Alzheimer's disease (AD), are posited to trigger synaptic dysfunction long before significant synaptic loss occurs in vulnerable circuits. Whereas soluble A beta aggregates from AD brain are well recognized potent synaptotoxins, less is known about the synaptotoxicity of soluble tau from AD or other tauopathy patient brains. Minimally manipulated patient-derived aqueous brain extracts contain the more diffusible native forms of these proteins. Here, we explore how intracerebral injection of A beta and tau present in such aqueous extracts of patient brain contribute to disruption of synaptic plasticity in the CA1 area of the male rat hippocampus. Aqueous extracts of certain AD brains acutely inhibited long-term potentiation (LTP) of synaptic transmission in a manner that required both A beta and tau. Tau-containing aqueous extracts of a brain from a patient with Pick's disease (PiD) also impaired LTP, and diffusible tau from either AD or PiD brain lowered the threshold for AD brain A beta to inhibit LTP. Remarkably, the disruption of LTP persisted for at least 2 weeks after a single injection. These findings support a critical role for diffusible tau in causing rapid onset, persistent synaptic plasticity deficits, and promoting A eta-mediated synaptic dysfunction.