Ectopic Cell Cycle Events Link Human Alzheimer's Disease and Amyloid Precursor Protein Transgenic Mouse Models

Abstract

Nerve cells that re-enter a cell cycle will die rather than divide, a fact that likely underlies the neurodegeneration in Alzheimer's disease (AD). Several mouse models of familial AD have been created, and although many display amyloid plaques in their brains, none captures the extensive pattern of nerve cell death found in the human disease. Using both immunocytochemistry and fluorescent in situ hybridization, we show that neurons in three different mouse models reproduce the ectopic cell cycling found in human AD. The temporal and spatial appearance of the cell cycle events in the mouse closely mimics the human disease progression. The cell-cycle events are evident 6 months before the first amyloid deposits and significantly precede the appearance of the first CD45ϩ microglia. These data suggest that the ectopic initiation of cell-cycle processes in neurons is an early sign of neuronal distress in both human and mouse AD. The close phenotypic correspondence indicates a previously unsuspected level of fidelity of the mouse model to the human disease. Finally, the relative timing suggests that neither the activated microglia nor the amyloid plaques themselves are necessary to initiate the pathogenic events in AD.

Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease

“…However, aberrant entry into the cell cycle has been reported to precede neuronal death in the cortex and CA3 regions at all stages of AD, from MCI to late stage AD and within AD mouse models (34). Further, expression of the ectopic cell-cycle proteins ultimately predicts the demise of these neurons (35). These findings are especially challenging for therapeutics targeting the regenerative potential of endogenous neural stem/progenitor populations, as an unintended side effect may be to promote ectopic entry of neurons into the cell cycle and thereby exacerbate neuron demise.…”

Cdk5 acts as a mediator of neuronal cell cycle re-entry triggered by amyloid-β and prion peptides

“…The abortive cell cycle re-entry has been reported in the brain of patients and in most AD animal models, 24,35,36 as well as in cultured neurons exposed to Aβ peptides. 23,35 Interestingly, in several pathologies in which ectopic cell cycle events have been described, Cdk5 overactivation also occurs.…”

“…Tau hyperphosphorylation was shown to be correlated with Cdk5 overactivation in experimental models of AD and PRE. 6,38 Recently it was reported that re-expression of cell cycle proteins in AD patients can occur prior to tau hyperphosphorylation, 11,36 and that cell cycle activation may contribute to the formation of NFTs, 39 which may be a sign of possible interconnection between both events. Moreover, some studies have also shown that abnormal tau phosphorylation precedes neuronal apoptotic death.…”

“…This difference between AD animal models and patients is further reinforced if we consider that the majority of the mouse models for this disease, although exhibiting one or even more of the neuropathological features of AD, fail to exhibit neuronal death. 36 Alterations in Rb phosphorylation also derive from a modification in the subcellular localization of Cdk4 and cyclin D1. membranes with ECF reagent for 5-10 min, on a Bio-Rad Versadoc 3000 Imaging System.…”

Confronting complexity in late‐onset Alzheimer disease: application of two‐stage analysis approach addressing heterogeneity and epistasis

“…Taumediated neurodegeneration in this area is thought to play a role in Alzheimer disease progression (Shahani N et al, 2006). Recent evidence is mounting in support of an alternative hypothesis for Alzheimer disease pathology, which implicates cell cycle reactivation as a key early event that precedes and possibly is causally related to tau, APP phosphorylation and apoptotic cell death (Andorfer C et al, 2005;McPhie DL et al, 2003;Yang Y et al, 2006). Amyloid precursor protein has been purported to regulate activation of neuronal cell cycle proteins (McPhie DL et al, 2003); therefore, hypothetically, mutations in VR22 could indirectly affect cell cycle activation, through interactions with APP (by way of beta-catenin and presenilin 1).…”