Elevated phospholipase D isoform 1 in Alzheimer's disease patients' hippocampus: Relevance to synaptic dysfunction and memory deficits

Abstract

IntroductionPhospholipase D (PLD), a lipolytic enzyme that breaks down membrane phospholipids, is also involved in signaling mechanisms downstream of seven transmembrane receptors. Abnormally elevated levels of PLD activity are well-established in Alzheimer's disease (AD), implicating the two isoforms of mammalian phosphatidylcholine cleaving PLD (PC-PLD1 and PC-PLD2). Therefore, we took a systematic approach of investigating isoform-specific expression in human synaptosomes and further investigated the possibility of therapeutic intervention using preclinical studies.MethodsSynaptosomal Western blot analyses on the postmortem human hippocampus, temporal cortex, and frontal cortex of AD patient brains/age-matched controls and the 3XTg-AD mice hippocampus (mouse model with overexpression of human amyloid precursor protein, presenilin-1 gene, and microtubule-associated protein tau causing neuropathology progressing comparable to that in human AD patients) were used to detect the levels of neuronal PLD1 expression. Mouse hippocampal long-term potentiation of PLD1-dependent changes was studied using pharmacological approaches in ex vivo slice preparations from wild-type and transgenic mouse models. Finally, PLD1-dependent changes in novel object recognition memory were assessed following PLD1 inhibition.ResultsWe observed elevated synaptosomal PLD1 in the hippocampus/temporal cortex from postmortem tissues of AD patients compared to age-matched controls and age-dependent hippocampal PLD1 increases in 3XTg-AD mice. PLD1 inhibition blocked effects of oligomeric amyloid β or toxic oligomeric tau species on high-frequency stimulation long-term potentiation and novel object recognition deficits in wild-type mice. Finally, PLD1 inhibition blocked long-term potentiation deficits normally observed in aging 3XTg-AD mice.DiscussionUsing human studies, we propose a novel role for PLD1-dependent signaling as a critical mechanism underlying oligomer-driven synaptic dysfunction and consequent memory disruption in AD. We, further, provide the first set of preclinical studies toward future therapeutics targeting PLD1 in slowing down/stopping the progression of AD-related memory deficits as a complementary approach to immunoscavenging clinical trials that are currently in progress.

Hippocampal stem cells promotes synaptic resistance to the dysfunctional impact of amyloid beta oligomers via secreted exosomes

“…Adult (6–8 weeks old) C57Bl/6 J mice were anesthetized with isoflurane and subjected to ICV injections using the freehand injection method [45, 50, 51]. Briefly, a 29-gauge needle, firmly held with hemostatic forceps to leave 4.5 mm of the needle tip exposed, was connected to a 25 μl Hamilton syringe via 0.38 mm polyethylene tubing.…”

“…NOR testing was performed as described previously [47, 50, 53]. Briefly, each mouse was habituated to an empty novel object recognition open field box that served to test each animal for normal locomotion.…”

Lipids and Alzheimer’s Disease

“…The synaptosomes from AD patients' temporal cortex and hippocampus showed an increase of PLD1 expression. The inhibition of PLD1 blocks the synaptic dysfunction in the hippocampus of 3xTg-AD mice in early-stage (Aβ driven) and late-stage (Aβ and tau driven) [151]. Expression of PLD3 is elevated in brain regions which are vulnerable to AD, including the hippocampus and cortex [152].…”

Amelioration of hippocampal dysfunction by adipose tissue‐targeted stem cell transplantation in a mouse model of type 2 diabetes

“…Acute brain slice methods described earlier (Ting, Daigle, Chen, & Feng, ) were modified as reported previously (Comerota, Tumurbaatar, Krishnan, Kayed, & Taglialatela, ; Krishnan, Kayed, & Taglialatela, ) to perform the field electrophysiology experiments described here. Mice were deeply anesthetized with isoflurane USP (5%—Cat # NDC 66794–017–10—Piramal Enterprises Limited—2014–2016) and transcardially perfused with 25–30 ml of room temperature carbogenated (95% O 2 and 5% CO 2 gas mixture artificial cerebrospinal fluid (ACSF) consisting of 92 mM N‐Methyl‐D‐Glucamine (NMDG—Cat # M2004—Sigma‐Aldrich—2013), 2.5 mM KCl (Cat # 793,590—Sigma‐Aldrich—2010), 1.25 mM NaH 2 PO 4 (Cat # S3139—Sigma‐Aldrich—2010), 30 mM NaHCO 3 (Cat # 792,519—Sigma‐Aldrich – 2010), 20 mM HEPES (Cat # RDD002—Sigma‐Aldrich—2012), 25 mM glucose (Cat # D9434—Sigma‐Aldrich—2007), 2 mM thiourea (Cat # T8656—Sigma‐Aldrich—2010), 5 mM +‐Na‐L‐ascorbate (Cat # A4034—Sigma‐Aldrich—2010), 3 mM Na pyruvate (Cat # 7,922,500—Sigma‐Aldrich—2010), 0.5 mM CaCl 2 .4H 2 O (Cat # 10043–52–4—Sigma‐Aldrich—2010) and 10 mM MgSO 4 .7H 2 O (Cat # M1880—Sigma‐Aldrich—2010), titrated to pH 7.3–7.4 with HCl (Cat # 320,331—Sigma‐Aldrich—2000).…”