Early Transient Neuronal CyclinD1 Expression Precedes Atrophy in the Frontal Cortex of APP23 Mice

The most common abnormalities found in Alzheimer’s disease (AD) brains are extracellular amyloid-β (Aβ) plaques and intracellular Neurofibrillary Tangles (NFTs), latter formed by aberrantly phosphorylated microtubule-associated protein tau. NFTs are predominantly found in the hippocampus and entorhinal cortex, and with lower densities elsewhere [1]. In addition to the Aβ plaques and NFTs, there is significant neuronal cell death with distinct regional variability [2-4]. The exact cellular events leading to neuronal cell death remain unclear, but several neuropathological studies linked neuronal death to unexpected reappearance of cell cycle events [5-7]. Ectopic neuronal cell cycle re-entry has been implicated in several other neurodegenerative conditions, including Parkinson’s disease [8], frontotemporal dementia [9], amyotrophic lateral sclerosis [10], and temporal lobe epilepsy [11], suggesting a possible common pathogenic mechanism. Ectopic activation of the cell cycle in post-mitotic neurons is thought to lead to neurodegeneration and cell death [9,12]. A crucial role of Aβ in cell cycle re-activation is supported by in vitro studies, and by expression of cell cycle proteins in mouse and rat cortical primary neurons challenged with Aβ [1315]. Other studies support a role of tau in neuronal cell death induced by cell cycle re-entry in vitro and in animal models [16-19]. Different transgenic mice expressing human Aβ Precursor Protein (APP) gene variants have been used to study the association of cell cycle-related protein expression and cell death in AD, with divergent results [20-22]. Because aberrant neuronal cell cycle re-entry is closely associated with sites of neuronal degeneration in human brains and mouse models of AD, we examined the expression of cell cycle markers in an APP transgenic mouse line (APP23) with Aβ plaque formation and cell loss. Accordingly, it has been reported that APP23 mice display neuronal death in specific areas of the brain that corresponds to those most affected in Alzheimer’s disease [23,24]. Our data show that neuronal cell cycle protein expression was focal in the frontal cortex of APP transgenic mice before amyloid plaque deposition, and it was associated with a subsequent volume reduction of the frontal cortex together with a disappearance of neuronal cell cycle protein expression. We also demonstrated that amyloid depositions in older APP23 mice were closely associated with cell cycle protein expression in astrocytes and microglia, but not neurons, consistent with reactive gliosis and inflammation linked to Aβ toxicity.