Cyclin C expression is involved in the pathogenesis of Alzheimer’s disease

Abstract

The expression of different cell cycle proteins in terminally differentiated neurons apparently precedes cell death or contributes to pathogenetic progression of Alzheimer’s disease (AD). Cyclins and cyclin-dependent kinases (Cdks), physiologically involved in mitotic processes of proliferating cells, are elevated in neurons prone to dedifferentiation and degeneration. Previously, it was shown that even inhibitors of the Cdks as p16^INK4a, p18^INK4c or p27^KIP1 are expressed in neurons of AD patients, indicating a rather complete involvement of cell cycle machinery in affected neurons. The aim of this study was to examine the involvement of the non-classical cyclin C in the pathogenetic process of AD. A marked elevated immunoreactivity of cyclin C was found both in neurons and astrocytes in AD. Increased levels of cyclin C RNA were detected by ribonuclease protection assay (RPA) in severe AD cases. Colocalization of cyclin C and its preferred binding partner, Cdk8, was only observed in astrocytes but not in neurons. The present observations suggest different cellular functions of cyclin C in neurons and astrocytes in AD.

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a loss of neurons, disturbances in the synaptic organization and aberrant axonal and dendritic sprouting, especially in brain areas highly involved in integrative processes such as hippocampal formation and limbic areas [5], [9], [32], [46], [59]. The process of degeneration is associated with an extracellular accumulation of senile plaques and an intracellular deposition of neurofibrillary tangles and neuropil threads [9], [32].

A variety of growth-associated [13], [47], [50] and growth-promoting factors [25], [27], [58], [66] and their receptors [58] are elevated in AD giving rise to activation of intracellular mitogenic pathways such as p21ras/MAPK. The p21ras/MAPK cascade in turn might be involved in pathological changes of phosphorylation and dephosphorylation processes leading to hyperphosphorylated tau or disturbed APP processing [14], [20], [28], [29]. In dividing non-neuronal cells, however, the p21ras/MAPK cascade is involved in mediating proliferation and differentiation signaling and cell cycle control. The rapid translocation of MAPK to the nucleus can activate the cyclin D/Cdk4 complex and results in the transition of cells from the G0 to the G1 phase of the cell cycle [34]. Recently, different cell cycle related proteins have been found in terminally differentiated neurons in the brain of AD patients, suggesting a dysfunction of cell cycle and differentiation control [1], [2], [3], [52], [53].

Elevated uncoordinated expression and activation of Cdk4 and its binding partner cyclin D in neurons [49] could force these cells to re-enter the cell cycle [39], initiating a process that might lead to hyperphosphorylation of tau, disturbance of APP processing and eventually to cell death [26], [31], [62]. Other cell cycle-dependent kinases such as Cdc2 [65] or Cdk5 [45], a unique member of the Cdk family, which has not yet been found involved in cell cycle regulation but functions in differentiated neurons, might contribute to this process [26], [31]. The pathogenetic cascade leading to activation of cell cycle-dependent kinases remains largely obscure.

Cell cycle related kinases are strongly regulated by higher-level so called secondary cyclins as cyclin H generating the CAK complex with Cdk7 and Mat1 [16], [21]. This complex can activate many Cdk/cyclin complexes immediately involved in the cell cycle progression as Cdk2, Cdk4 or Cdc2 [22]. While, recently, Cdk7 has been found involved in AD [67], no data are available on cyclin C or its main binding partner Cdk8 with respect to AD. In the present study, we thus analyzed changes in the expression of cyclin C in AD.