Human secreted tau increases amyloid-beta production

Abstract

The interaction of amyloid-beta (Aβ) and tau in the pathogenesis of Alzheimer's disease is a subject of intense inquiry, with the bulk of evidence indicating that changes in tau are downstream of Aβ. It has been shown however, that human tau overexpression in amyloid precursor protein transgenic mice increases Aβ plaque deposition. Here, we confirm that human tau increases Aβ levels. To determine if the observed changes in Aβ levels were because of intracellular or extracellular secreted tau (eTau for extracellular tau), we affinity purified secreted tau from Alzheimer's disease patient-derived cortical neuron conditioned media and analyzed it by liquid chromatography-mass spectrometry. We found the extracellular species to be composed predominantly of a series of N-terminal fragments of tau, with no evidence of C-terminal tau fragments. We characterized a subset of high affinity tau antibodies, each capable of engaging and neutralizing eTau. We found that neutralizing eTau reduces Aβ levels in vitro in primary human cortical neurons where exogenously adding eTau increases Aβ levels. In vivo, neutralizing human tau in 2 human tau transgenic models also reduced Aβ levels. We show that the human tau insert sequence is sufficient to cause the observed increase in Aβ levels. Our data furthermore suggest that neuronal hyperactivity may be the mechanism by which this regulation occurs. We show that neuronal hyperactivity regulates both eTau secretion and Aβ production. Electrophysiological analysis shows for the first time that secreted eTau causes neuronal hyperactivity. Its induction of hyperactivity may be the mechanism by which eTau regulates Aβ production. Together with previous findings, these data posit a novel connection between tau and Aβ, suggesting a dynamic mechanism of positive feed forward regulation. Aβ drives the disease pathway through tau, with eTau further increasing Aβ levels, perpetuating a destructive cycle.

Tau immunotherapy for Alzheimer's disease

“…The N-terminal cleavage at Asp13 and the C-terminal cleavage at Glu391 are considered late events in the pathogenesis [33,34]. Recently, an additional N-terminal fragment (residues 1-224) was identified in CSF from patients with AD and PSP, and has been hypothesized to be an early marker of disease and particularly pathogenic [35,36]. A similar calpain-cleaved fragment was reported by other groups [37,38].…”

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

“…If this observation can be appropriately validated and explored in a separate larger patient cohort, it may suggest a stark difference in the role of A β 1‐42 in FTLD‐tau compared to FTLD‐TDP. There is evidence that extracellular tau regulates neuronal production of amyloid beta, by mediating neuronal hyperactivity 38. Thus, the predictive value of A β 1‐42 may reflect the downstream impact of extracellular tau rather than the direct role of A β 1‐42 in FTD pathophysiology.…”

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

“…In this sense, there are 3 anti-tau antibodies currently being studied in phase I trials (Table 1). BMS-986168 targets extracellular, N-terminally fragmented forms of tau (eTau) that can induce an increase in Aβ production and contribute to the spreading of the pathology [87]. This antibody reportedly neutralizes eTau toxicity in mouse models of FTD.…”