In our sequential model for tau and

In our sequential model for tau and Aβ deposition, we included the tau deposition in the medial temporal glycosylase inhibitor in the absence of Aβ deposition, which is a pathological definition of primary age-related tauopathy (PART). Although the tau pathologies in PART and AD are almost identical in their neuropathology, ultrastructure, and tau isoforms (Crary et al., 2014), it is still uncertain whether PART is a separate entity or premonitory state of AD (Crary et al., 2014, Duyckaerts et al., 2015). We could not determine a way to separate participants with PART from those presumed to be AD. A long-term follow-up study monitoring the spatial expansion of tau and Aβ will identify the temporal sequence of accumulation of the 2 pathologies leading to the progression of AD and thereby provide answers to the unsolved questions: does neocortical Aβ promote the spreading of tau to the neocortex distant from the medial temporal cortex? And, is the PART an element of AD spectrum?
Conclusions
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Acknowledgements
Introduction Alzheimer’s disease (AD) is characterized by accumulation of intraneuronal neurofibrillary tangles composed of the microtubule-associated protein tau and extracellular deposition of the amyloid β-protein (Aβ) as amyloid plaques and vascular amyloid [39]. Despite recent progress in symptomatic therapy using cholinergic drugs and N-methyl-d-aspartate receptor antagonist, there are currently no effective therapeutic approaches that directly modify the neurodegenerative processes of AD (disease-modifying therapies, DMTs). Research in this area has focused mainly on agents that disrupt the accumulation of Aβ and tau in the CNS [5]. Aβ is widely believed to be a major factor in AD pathogenesis (the amyloid hypothesis) based on human genetic analyses, in vitro biochemical and cell viability studies, and a myriad of neurophysiological and behavior studies in animal models, particularly Aβ transgenic mice [3], [39], [40]. Two major forms of Aβ are produced in AD, the 40-amino acid Aβ1-40 and 42-amino acid Aβ1-42 residues are produced, but the relative amount of Aβ1-42 is particularly critical for AD progression because this longer form is more prone to aggregate than the shorter peptide [16], [39]. Aβ molecules tend to aggregate and form oligomers and mature fibrils [25], [32], [49]. These Aβ aggregates may cause neuronal injury directly by acting on synapses or indirectly by activating microglia and astrocytes; therefore, several pharmacological approaches for DMT have been developed that target the sequential events in Aβ production [25], [27], [32], [40], [42], [48], [49]. Cilostazol (CSZ) (Fig. 1), a selective inhibitor of phosphodiesterase type-3 (PDE3), acts as an antiplatelet agent and is used for the prevention of cerebral ischemia in Japan and other Asian countries [8], [10]. It was also reported that CSZ slows cognitive decline in patients with AD and cerebrovascular diseases [14], [37], [44], [45]. In a pilot study including 10 patients with moderate AD receiving the acetylcholinesterase inhibitor donepezil, add-on CSZ treatment for 5–6 months significantly increased Mini Mental State Examination (MMSE) score compared to baseline [2]. In a larger pilot study (30 participants, 12 months), CSZ add-on therapy improved cognitive impairments in patients with stable AD [45]. In addition, CSZ was shown to be effective against cognitive decline in AD patients with cerebrovascular diseases [37] as well as mild cognitive impairment (MCI) [44]. It has also been shown that CSZ decreases Aβ25-35 accumulation and attenuates Aβ25-35-induced cognitive deficits in animal models of AD [11], [35]. Recently, we reported that CSZ suppressed Aβ-induced neurotoxicity in SH-SY5Y cells through inhibition of oxidative stress as evidenced by reduced reactive oxygen species (ROS) accumulation, nicotinamide adenine dinucleotide phosphate oxidase (Nox) activity, and mitogen-activated protein kinase (MAPK) signaling [24].