The relationship between adult hippocampal neurogenesis and cognitive impairment in Alzheimer's disease

Abstract

Neurogenesis persists throughout adulthood in the hippocampus and contributes to specific cognitive functions. In Alzheimer's disease (AD), the hippocampus is affected by pathology and functional impairment early in the disease. Human AD patients have reduced adult hippocampal neurogenesis (AHN) levels compared to age-matched healthy controls. Similarly, rodent AD models show a decrease in AHN before the onset of the classical hallmarks of AD pathology. Conversely, enhancement of AHN can protect against AD pathology and ameliorate memory deficits in both rodents and humans. Therefore, impaired AHN may be a contributing factor of AD-associated cognitive decline, rather than an effect of it. In this review we outline the regulation and function of AHN in healthy individuals, and highlight the relationship between AHN dysfunction and cognitive impairments in AD. The existence of AHN in humans and its relevance in AD patients will also be discussed, with an outlook toward future research directions. HIGHLIGHTS: Adult hippocampal neurogenesis occurs in the brains of mammals including humans. Adult hippocampal neurogenesis is reduced in Alzheimer's disease in humans and animal models.

Keywords: Alzheimer's disease; adult hippocampal neurogenesis; cognition; hippocampus; learning and memory.

FIGURE 1

The AHN trajectory in mice from type 1 stem cells to mature dentate granule cells, along with the associated cell markers per cell type. AHN, adult hippocampal neurogenesis; SGZ, subgranular zone.

FIGURE 2

AHN and associated cognitive function is disrupted in transgenic rodent models of AD. These include changes in proliferation, differentiation, neuronal maturation, and functional changes in AHN‐associated cognitive functions such as spatial learning and memory assessed using the Morris water maze test. AD, Alzheimer's disease; AHN, adult hippocampal neurogenesis.

FIGURE 3

Proposed mechanisms underpinning the AD‐driven impairment of AHN. Many different regulators of AHN are proposed to be affected by AD pathology, such as mitochondrial dysfunction, impaired calcium homeostasis and reactive oxygen species, transcription factor dysregulation, neurotransmitters, and neuronal signaling impairments and Aβ plaques and neurofibrillary tangles. Aβ, amyloid beta; AD, Alzheimer's disease; AHN, adult hippocampal neurogenesis.