Pathological Nuclear Hallmarks in Dentate Granule Cells of Alzheimer's Patients: A Biphasic Regulation of Neurogenesis.

The dentate gyrus (DG) of the human hippocampus is a complex and dynamic structure harboring mature and immature granular neurons in diverse proliferative states. While most mammals show persistent neurogenesis through adulthood, human neurogenesis is still under debate. We found nuclear alterations in granular cells in autopsied human brains, detected by immunohistochemistry. These alterations differ from those reported in pyramidal neurons of the hippocampal circuit. Aging and early AD chromatin were clearly differentiated by the increased epigenetic markers H3K9me3 (heterochromatin suppressive mark) and H3K4me3 (transcriptional euchromatin mark). At early AD stages, lamin B2 was redistributed to the nucleoplasm, indicating cell-cycle reactivation, probably induced by hippocampal nuclear pathology. At intermediate and late AD stages, higher lamin B2 immunopositivity in the perinucleus suggests fewer immature neurons, less neurogenesis, and fewer adaptation resources to environmental factors. In addition, senile samples showed increased nuclear Tau interacting with aged chromatin, likely favoring DNA repair and maintaining genomic stability. However, at late AD stages, the progressive disappearance of phosphorylated Tau forms in the nucleus, increased chromatin disorganization, and increased nuclear autophagy support a model of biphasic neurogenesis in AD. Therefore, designing therapies to alleviate the neuronal nuclear pathology might be the only pathway to a true rejuvenation of brain circuits.

Aging and Alzheimer's disease connection: Nuclear Tau and lamin A.

Age-related pathologies like Alzheimer`s disease (AD) imply cellular responses directed towards repairing DNA damage. Postmitotic neurons show progressive accumulation of oxidized DNA during decades of brain aging, which is especially remarkable in AD brains. The characteristic cytoskeletal pathology of AD neurons is brought about by the progressive changes that neurons undergo throughout aging, and their irreversible nuclear transformation initiates the disease. This review focusses on critical molecular events leading to the loss of plasticity that underlies cognitive deficits in AD. During healthy neuronal aging, nuclear Tau participates in the regulation of the structure and function of the chromatin. The aberrant cell cycle reentry initiated for DNA repair triggers a cascade of events leading to the dysfunctional AD neuron, whereby Tau protein exits the nucleus leading to chromatin disorganization. Lamin A, which is not typically expressed in neurons, appears at the transformation from senile to AD neurons and contributes to halting the consequences of cell cycle reentry and nuclear Tau exit, allowing the survival of the neuron. Nevertheless, this irreversible nuclear transformation alters the nucleic acid and protein synthesis machinery as well as the nuclear lamina and cytoskeleton structures, leading to neurofibrillary tangles formation and final neurodegeneration.