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

Amyloid β protein (Aβ) 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 Aβ 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 Aβ 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 Aβ 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 Aβ 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 Aβ-mediated synaptic dysfunction.

SIGNIFICANCE STATEMENT The microtubule-associated protein tau forms relatively insoluble fibrillar deposits in the brains of people with neurodegenerative diseases including Alzheimer's and Pick's diseases.

More soluble aggregates of disease-associated tau may diffuse between cells and could cause damage to synapses in vulnerable circuits.

We prepared aqueous extracts of diseased cerebral cortex and tested their ability to interfere with synaptic function in the brains of live rats.

Tau in these extracts rapidly and persistently disrupted synaptic plasticity and facilitated impairments caused by amyloid β protein, the other major pathologic protein in Alzheimer's disease.

These findings show that certain diffusible forms of tau can mediate synaptic dysfunction and may be a target for therapy.