"" Phosphodiesterase as a Drug Target of Alzheimer’s Disease

Mini Review

Austin Alzheimers J Parkinsons Dis. 2015;2(1): 1021.

Phosphodiesterase as a Drug Target of Alzheimer’s Disease

Fuyuki Kametani*

Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Japan

*Corresponding author: Fuyuki Kametani, Department of Dementia and Higher Brain Function Research, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan

Received: December 12, 2014; Accepted: July 10, 2015; Published: July 26, 2015

Abstract

Although amyloid hypothesis is widely accepted, recent findings indicate that the hypothesis may be incorrect, suggesting that Aβ is not a suitable drug target in Alzheimer’s disease. Accumulating evidences and new findings suggest that phosphodiesterases is involved in Alzheimer’s disease. In this review, I introduce the current state of phosphodiesterases and their inhibitors as for Alzheimer’s research.

Keywords: Amyloid; Alzheimer’s disease; Phosphodiesterase; Phosphodiesterase inhibitor; Aβ; cAMP; cGMP; Signal transduction; Therapy; Drug

Abbreviations

AD: Alzheimer’s Disease; FAD: Familial Alzheimer’s Disease; APP: Amyloid Precursor Protein; PDE: Phosphodiesterase; cAMP: Cyclic Adenosine Monophosphate; cGMP: Cyclic Guanosine Monophosphate; PKA: cAMP-dependent Protein Kinase; CREB: cAMP Response Element-Binding Protein; AC: Adenylate Cyclases; sGC: Soluble Guanylyl Cyclase; cGKs: cGMP-dependent Protein Kinases; CNG: Cyclic Nucleotide-gated; HCN: Hyperpolarizationactivated Cyclic Nucleotide; CTF: C-terminal Fragments

Introduction

According to the widely accepted amyloid hypothesis, amyloid-β (Aβ) production from amyloid precursor protein (APP) and Aβ amyloid fibril formation are considered the primary causes of Alzheimer’s disease (AD). However, Aβ peptides are normal metabolic components, and there is little evidence that Aβ is neurotoxic at in vivo concentrations [1]. No significant correlations between the concentration or the brain distribution of neuritic plaques and the degree of dementia, loss of neurons, the distribution of dystrophic neurites, or cytoskeletal abnormality have been obtained [2-4]. The levels of soluble Aβ including oligomeric species of Aβ are significantly greater in younger adults than older adults with or without AD [5]. Recent neuroimaging studies have revealed that amyloid deposits are present in cognitively normal individuals, whereas some AD patients showed no amyloid deposits in a positron emission tomography analysis [6,7]. In addition, all Aβ amyloidfocused clinical trials have failed [8]. Together these finding indicate that the amyloid hypothesis may be incorrect. Is Aβ thus a suitable target for AD drug development?

Phosphodiesterase inhibitor as a drug for cognitive enhancement

To date, the use of many inhibitors of phosphodiesterase (PDE) has been reported to produce cognitive enhancement. Accumulating evidence indicates that the inhibition of PDE activity may be an appropriate target for AD. The effectiveness of the administration of PDE inhibitors has been demonstrated in several animal models of AD and in clinical trials as shown in Table 1.

Citation: Kametani F. Phosphodiesterase as a Drug Target of Alzheimer’s Disease. Austin Alzheimers J Parkinsons Dis. 2015;2(1): 1021. ISSN: 2377-357X