Cerebral Phospho-Tau Acts Synergistically with Soluble Aβ42 Leading to Mild Cognitive Impairment in AAV-AD Rats.

Abstract

BACKGROUND:

Alzheimer's disease (AD) is a continuum of events beginning with an increase in brain soluble Aβ42 followed by the appearance of hyperphosphorylated tau (P-tau, asymptomatic stage). Mild Cognitive Impairment (MCI) then appears (prodromal stage). However, the individual contribution of these two soluble proteins in the onset of the first cognitive symptoms remains unclear.

OBJECTIVES:

We sought to understand the specific impact of p-tau on the development of MCI in the AAV-AD rat model, a model of late-onset Alzheimer's disease (LOAD) predementia.

METHODS:

We specifically reduced the phosphorylation level of tau while leaving Aβ42 levels unchanged using a DYRK1A protein kinase inhibitor, Leucettine L41, in an adeno-associated virus-based Alzheimer's disease (AAV-AD) rat model. Leucettine L41 was administered by intraperitoneal injection at 20 mg/kg per day in AAV-AD rats from 9 (late asymptomatic phase) to 10 (prodromal phase) months of age.

RESULTS:

Decreased soluble forms of P-tau induced by chronic administration of Leucettine L41 did not change soluble Aβ42 levels but prevented MCI onset in 10-month-old AAV-AD rats.

CONCLUSIONS:

The present study argues that P-tau is required to induce the development of MCI. Consistent with our previous findings that soluble Aβ42 is also required for MCI onset, the data obtained in the AAV-AD rat model confirm that the transition from the asymptomatic to the prodromal stage may be caused by the combined presence of both soluble brain forms of Aβ42 and p-tau, suggesting that the development of MCI may be the consequence of their synergistic action.

• Authors: B Souchet, M Audrain, Y Gu, M F Lindberg, N S Orefice, E Rey, N Cartier, N Janel, L Meijer, J Braudeau
• Journal: The journal of prevention of Alzheimer's disease (J Prev Alzheimers Dis) Vol. 9 Issue 3 Pg. 480-490 ( 2022) ISSN: 2426-0266 [Electronic] Switzerland
• PMID: 35841249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Peptide Fragments
• amyloid beta-protein (1-42)
• tau Proteins

Topics

• Alzheimer Disease (diagnosis)
• Amyloid beta-Peptides
• Animals
• Cognitive Dysfunction (psychology)
• Humans
• Peptide Fragments
• Prodromal Symptoms
• Rats
• tau Proteins (metabolism)