In people with Alzheimer’s disease and other tauopathies, tau can accumulate at post-synapses in the dendrites of neurons. Could eliminating this tau temper neurodegeneration? In the May 26 Science Translational Medicine, researchers led by Natura Myeku, Columbia University, New York, reported that stimulating the postsynaptic G protein-coupled receptor (PAC1R) in a mouse model of tauopathy prompted the proteasome to digest tau. The treated mice performed better on memory tasks. Given that postsynaptic tau seeded more tangles in cultured neurons than did tau from pre-synapses, Myeku and colleagues believe that targeting PAC1R, and maybe other postsynaptic GPCRs, could become a treatment strategy.
- Postsynaptic tau from human and mouse brain seeds tangles in cultured neurons.
- Activating PAC1R boosts proteasome activity in mouse dendrites.
- As the proteasome clears tau, cognition improves.
As a postdoc with co-author Karen Duff, who is now at University College London, Myeku had previously shown that raising cyclic AMP levels boosted activity of protein kinase A (PKA), which then stimulated the proteasome. In 4-month-old rTg4510 mice, this cleared tangles and improved learning and memory (Dec 2015 news). But since cAMP is in almost every part of every cell, how to specifically ramp it up in the dendrites where tau accumulates?
The researchers homed in on receptors primarily expressed at the post-synapses, such as PAC1R. First author Ari Schaler and colleagues now report that rTg4510 mice treated with the neuropeptide PACAP, which activates PAC1R, ramped up proteasome activity in dendrites and lowered tau in postsynaptic fractions of mouse cortical tissue. Treated mice better navigated a water maze than did untreated controls, and they better remembered objects placed into their cages. Alzforum first reported the finding when Duff presented at an EMBL Symposium held in Heidelberg, Germany (Jul 2017 conference news).
Now, the scientists report that tau accumulating in postsynapses may be particularly pathogenic. They took brain tissue from rTg4510 mice and isolated tau from pre- and postsynaptic fractions. In cell-based seeding assays, tangles bloomed when postsynaptic tau was added to cell medium, but not when presynaptic tau was used (see image below).
The same was true for extracts taken postmortem from cortical tissue of six people who had had AD. The postsynaptic fraction seeded more readily. “Postsynaptic compartments accumulate a lot of tau, and it seems to be more toxic. It’s a double whammy,” Myeku said.
Post Is Worse. Tau taken from postsynapses of 3-, 5-, or 8-month-old tauopathy mice seeded more tangles in HEK cells (bottom) than tau taken from the presynaptic fraction (top). [Courtesy of Schaler et al., Science Translational Medicine, 2021.]
The findings hint that it may be better to target tau in the post-synapse than elsewhere. But how? Though PACAP itself slips through the blood-brain barrier and has even been reported to prevent cognitive decline in animal models of amyloidosis and Parkinson’s, it is quickly degraded in the blood and would have to be directly administered directly into the brain (Rat et al., 2011; Nonaka et al., 2012; de Souza et al., 2020). Myeku believes targeting PAC1R with a small molecule or compound more stable than the PACAP peptide might work, but recognizes the difficulty. “It may be challenging to target PAC1R with small molecules because of its large binding pocket,” she told Alzforum.
In the meantime, the researchers are exploring other GPCRs at the post-synapse. One is the 5-HT4 serotonin receptor. It activates the proteasome by stimulating cAMP and PKA, just as PAC1R does. The FDA has approved 5-HT4 agonists for other conditions, and Myeku is testing one, called prucalopride, in PS19 mice. Prucalopride improves gut motility and is prescribed for constipation. Other serotonin receptors have been targeted in AD, to no avail.—Chelsea Weidman Burke
Research Models Citations
- Protecting Proteasomes from Toxic Tau Keeps Mice Sharp
- A New Explanation for Dendritic Tau: It’s Made There
- Rat D, Schmitt U, Tippmann F, Dewachter I, Theunis C, Wieczerzak E, Postina R, Van Leuven F, Fahrenholz F, Kojro E. Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer's disease-like pathology in amyloid precursor protein-transgenic mice. FASEB J. 2011 Sep;25(9):3208-18. PubMed.
- Nonaka N, Farr SA, Nakamachi T, Morley JE, Nakamura M, Shioda S, Banks WA. Intranasal administration of PACAP: Uptake by brain and regional brain targeting with cyclodextrins. Peptides. 2012 Aug;36(2):168-75. PubMed.
- de Souza FR, Ribeiro FM, d' Almeida Lima PM. Implications of VIP and PACAP in Parkinson's disease: what do we know so far?. Curr Med Chem. 2020 Mar 20; PubMed.
- Schaler AW, Runyan AM, Clelland CL, Sydney EJ, Fowler SL, Figueroa HY, Shioda S, Santa-Maria I, Duff KE, Myeku N. PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain. Sci Transl Med. 2021 May 26;13(595) PubMed.