Increased hippocampal neurogenesis in Alzheimer's disease

Abstract

Neurogenesis, which persists in the adult mammalian brain, may provide a basis for neuronal replacement therapy in neurodegenerative diseases like Alzheimer's disease (AD). Neurogenesis is increased in certain acute neurological disorders, such as ischemia and epilepsy, but the effect of more chronic neurodegenerations is uncertain, and some animal models of AD show impaired neurogenesis. To determine how neurogenesis is affected in the brains of patients with AD, we investigated the expression of immature neuronal marker proteins that signal the birth of new neurons in the hippocampus of AD patients. Compared to controls, Alzheimer's brains showed increased expression of doublecortin, polysialylated nerve cell adhesion molecule, neurogenic differentiation factor and TUC-4. Expression of doublecortin and TUC-4 was associated with neurons in the neuroproliferative (subgranular) zone of the dentate gyrus, the physiological destination of these neurons (granule cell layer), and the CA1 region of Ammon's horn, which is the principal site of hippocampal pathology in AD. These findings suggest that neurogenesis is increased in AD hippocampus, where it may give rise to cells that replace neurons lost in the disease, and that stimulating hippocampal neurogenesis might provide a new treatment strategy.

Fig. 1.

Plaques and NFTs in hippocampus of AD brain. Plaques, detected with antibodies against Aβ (blue) and APP (brown) (A), were surrounded by phospho-τ-immunopositive nerve terminals (B). NFTs delineated with anti-phospho-τ are shown at higher magnification in C.

Fig. 2.

Expression of neuronal marker proteins in AD hippocampus. Protein from control (Con) and AD hippocampus was used for Western blotting with antibodies against the indicated proteins and actin was used as a control for consistency of protein loading. Early, Moderate, and Severe refer to AD of increasing histopathological severity. Band intensities were quantified by computer-assisted densitometry to give average values (fold increase over same-gel control), as reported in Results.

Fig. 3.

Immunohistochemical evidence for increased neurogenesis in hippocampus of AD brains. (A) TUC-4 and DCX are expressed in the SGZ of control and AD brain (arrows), but only in AD are large numbers of TUC-4- and DCX-immunopositive cells observed in GCL (*). Immunoreactive cells in the SGZ show shrunken cytoplasm and condensed nuclei, which is consistent with death of cells that do not transit to the GCL; a similar finding was observed in aged control brains (data not shown). (B) DCX-immunopositive cells (arrow) can also be detected in CA1 (Left, low power; Right, high power) of AD hippocampus. (C) Cells in SGZ express the 10-kDa caspase-8 cleavage product (arrow), suggesting caspase-dependent programmed cell death.

Fig. 4.

Colocalization of multiple markers of neuronal lineage in TUC-4- and DCX-immunopositive cells from DG of AD brains. Confocal imaging shows colocalization of TUC-4 (green) and Hu (red) (A) and of DCX (red) and PSANCAM (green) (B). Nuclei were counterstained with DAPI (blue).