Abstract
Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite extensive research and targeting of the main molecular components of the disease, beta-amyloid (Aβ) and tau, there are currently no treatments that alter the progression of the disease. Here, we examine the effects of two specific kinase inhibitors for calcium/calmodulin-dependent protein kinase type 1D (CaMK1D) on Aβ-mediated toxicity, using mouse primary cortical neurons. Tau hyperphosphorylation and cell death were used as AD indicators. These specific inhibitors were found to prevent Aβ induced tau hyperphosphorylation in culture, but were not able to protect cells from Aβ induced toxicity. While inhibitors were able to alter AD pathology in cell culture, they were insufficient to prevent cell death. With further research and development, these inhibitors could contribute to a multi-drug strategy to combat AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative condition which is the most common cause of dementia worldwide [1]
We explore the feasibility of using specific inhibitors for calcium/calmodulin-dependent protein kinase type 1D (CaMK1D) to prevent AD pathology in a cell culture model
Hyperphosphorylated tau gains a toxic function. It aggregates in the cytoplasm of neurons into structures such as single straight filaments and paired helical filaments, which subsequently lead to the formation of neurofibrillary tangles (NFT) [12]
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative condition which is the most common cause of dementia worldwide [1]. The amyloid cascade hypothesis suggests that sporadic AD is caused by a sequence of events resulting directly from the action of these Aβ peptides, oligomers, and/or plaques Another well-studied hypothesis regarding the root cause of AD is the tau hypothesis. It aggregates in the cytoplasm of neurons into structures such as single straight filaments and paired helical filaments, which subsequently lead to the formation of neurofibrillary tangles (NFT) [12]. This work, the effects of CaMK1D inhibitors on AD-like indicators in Aβ treated primary neurons were examined, taking into account the major AD hypotheses outlined above. While cell viability did not appear to be affected by the presence of inhibitors at non-toxic concentrations, the phosphorylation of tau was reduced to near control levels. FFiigguurree33..EEfffeeccttooffvvaarryyiinnggccoonncceennttrraattiioonnssooffCCaaMMKK11DDiinnhhiibbiittoorrssoonnpprriimmaarryynneeuurroonnss..VViaiabbiilliittyyooffmmoouusseepprriimmaarryyccoorrtticicaall nneeuurroonnsswwaassmmeaesausruerdedbybyMMTTTaTssaasys.aTy.heThreespreosnpsoenfsreomfrocmellscetrllesaterdeawteidthwniothCnaMo KC1aDMKin1hDibitnohrisbwitoasrsnworams anliozremdatloiz1e0d0%to v1i0a0b%ilitvyi.aRbielsituyl.tsRoesfuthltrseoefstehpraeerasteepMarTaTteaMssTaTy atrsisaalys utrsiianlsgu(Asin) gCS(A58)7CaSn5d87(Ban) dCS(B6)40C.S(6C4)0R. (eCsu) RltsesoufltMs TofTMasTsTayasssuasyisngustihneg inthheibinithoirbsiatot rhsigaht ehrigchoenrcecnotnrcaetinotnras,tiuopnst,ou1p0 tμoM1.0(μDM) R. e(Dsu)ltRseosfuoltnseoLf DonHe aLsDsaHy tarsisaalywtirtihalCwS6it4h0.CPSo6i4n0t.sPreopinrtessernept rtheseemntetahne omf seiaxnreopf lsiicxatreesp,laicnadteesr,raonrdbaerrsrorrepbraerssernetpsrteasnednatrsdtadnedvairadtiodne.viation
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