Phosphodiesterase PDE4D Is Decreased in Frontal Cortex of Aged Rats and Positively Correlated With Working Memory Performance and Inversely Correlated With PKA Phosphorylation of Tau

Abstract

Age is the largest risk factor for Alzheimer's disease (AD) and contributes to cognitive impairment in otherwise healthy individuals. Thus, it is critical that we better understand the risk aging presents to vulnerable regions of the brain and carefully design therapeutics to address those effects. In this study we examined age-related changes in cAMP-regulatory protein, phosphodiesterase 4D (PDE4D). Inhibition of PDE4D is currently under investigation as a therapeutic target for AD based on memoryenhancing effects in rodent hippocampus. Therefore, it is important to understand the role of PDE4D in brain regions particularly vulnerable to disease such as the frontal association cortex (FC), where cAMP signaling can impair working memory via opening of potassium channels. We found that PDE4D protein level was decreased in the FC of both moderately and extremely aged rats, and that PDE4D level was correlated with performance on a FC-dependent working memory task. In extremely aged rats, PDE4D was also inversely correlated with levels of phosphorylated tau at serine 214 (S214), a site phosphorylated by protein kinase A. In vitro studies of the PDE4D inhibitor, GEBR-7b, further illustrated that inhibition of PDE4D activity enhanced phosphorylation of tau. pS214-tau phosphorylation is associated with early AD tau pathology, promotes tau dissociation from microtubules and primes subsequent tau hyperphosphorylation at other critical AD-related sites. Age-related loss of PDE4D may thus contribute to the specific vulnerability of the FC to degeneration in AD, and play a critical role in normal cAMP regulation, cautioning against the use of pan-PDE4D inhibitors as therapeutics.

Age‐related calcium dysregulation linked with tau pathology and impaired cognition in non‐human primates

“…It is noteworthy that PDE4D inhibitors are currently under development as potential treatments for AD 50 ; the current data, as well as recent findings showing that age-related decreases in PDE4D in rodent PFC correlate with elevated tau phosphorylation, caution that this strategy may actually worsen rather than alleviate tau pathology in vulnerable brain regions. 51 Alternative strategies may aim to restore regulation of calcium-cAMP signaling, for example, with GCPII inhibitors, 52 or re-stabilizing pS2808-RyR2 to reduce calcium leak. Chronic S107 treatment in an AD mouse model has been shown to improve behavioral performance on tests of hippocampal function.…”

Studies of aging nonhuman primates illuminate the etiology of early‐stage Alzheimer's‐like neuropathology: An evolutionary perspective

“…The expansion of the association cortices corresponds with an increase in AD neuropathology that can be seen across species (Table 1). There is little tau pathology in wild-type rodents, with aged rats, but not mice, producing pS214, but not more hyperphosphorylated sites (Carlyle et al, 2014;Leslie et al, 2020).…”

“…The expansion of the association cortices corresponds with an increase in AD neuropathology that can be seen across species (Table 1 ). There is little tau pathology in wild‐type rodents, with aged rats, but not mice, producing pS214, but not more hyperphosphorylated sites (Carlyle et al, 2014 ; Leslie et al, 2020 ). Very old marmosets express hyperphosphorylated tau labeled by the Alz50 and AT100 antibodies (Rodriguez‐Callejas et al, 2016 ), but this labeling appears to become fibrillar only in the very oldest animals (Rodriguez‐Callejas et al, 2016 ).…”

“…Carlyle et al, 2014 ; Datta, Enwright, et al, 2020 ; Datta, Leslie, et al, 2020 ; Jin et al, 2018 ). Importantly, the expression of these regulatory proteins is reduced in the aged PFC in both animals and humans (Carlyle et al, 2014 ; Datta, Enwright, et al, 2020 ; Datta, Leslie, et al, 2020 ; García‐Bea et al, 2016 ; Hernandez et al, 2018 ; Leslie et al, 2020 ; Lu et al, 2004 ), rendering the association cortices vulnerable to dysregulated cAMP‐calcium signaling.…”

“…There are also differences in tau pathology across species, where the degree of pathology corresponds with the extent of expansion of the association cortex: wild type rodents < marmosets < macaques < chimpanzees < humans (Braak & Braak, 1991 ; Carlyle et al, 2014 ; Edler et al, 2017 ; Leslie et al, 2020 ; Paspalas et al, 2018 ; Rodriguez‐Callejas et al, 2016 ). We propose that the evolutionary changes that expanded the association cortices and allowed the generation of sustained mental representations underlying abstract thought confer vulnerability for tau pathology when molecular regulation is lost with inflammation and advancing age.…”