Dendritic Spines: Mediators of Cognitive Resilience in Aging and Alzheimer's Disease

Abstract

Cognitive resilience is often defined as the ability to remain cognitively normal in the face of insults to the brain. These insults can include disease pathology, such as plaques and tangles associated with Alzheimer's disease, stroke, traumatic brain injury, or other lesions. Factors such as physical or mental activity and genetics may contribute to cognitive resilience, but the neurobiological underpinnings remain ill-defined. Emerging evidence suggests that dendritic spine structural plasticity is one plausible mechanism. In this review, we highlight the basic structure and function of dendritic spines and discuss how spine density and morphology change in aging and Alzheimer's disease. We note evidence that spine plasticity mediates resilience to stress, and we tackle dendritic spines in the context of cognitive resilience to Alzheimer's disease. Finally, we examine how lifestyle and genetic factors may influence dendritic spine plasticity to promote cognitive resilience before discussing evidence for actin regulatory kinases as therapeutic targets for Alzheimer's disease.

Keywords: Alzheimer’s disease; actin cytoskeleton; aging; cognitive resilience; dendritic spine.

Figure 1.

Representative microscope images and corresponding three-dimensional digital reconstruction models of dendrites. A) Representative maximum-intensity confocal image of a dye-filled dendrite from a mouse hippocampus pyramidal neuron after deconvolution. Scale bars represent 5 μm. Three-dimensional digital reconstruction of the dendrite is depicted below the image. Reconstruction was generated in Neurolucida360. Colors correspond to dendritic protrusion classes: blue represents thin spines; orange, stubby spines; green, mushroom spines; and yellow, dendritic filopodia. Neurolucida360 classifies dendritic spines using the following criteria: mushroom spines have a head-to-neck ratio > 1.1 and head diameter > 0.35 μm; thin spines have a head-to-neck ratio < 1.1, spine length < 3 μm, and either length-to-head ratio > 2.5 or head diameter < 0.35 μm; filopodia are those structures that meet the same measurements as thin spines, but are > 3 μm long. B) Representative bright-field image of Golgi impregnated dendrite from human postmortem prefrontal cortex tissue sample. Three-dimensional digital reconstruction of the same dendrite is depicted below the image. C) Representative illustration of dendrite featuring mushroom, thin, and stubby spines.

Figure 2.

Rho signaling pathways regulate dendritic spine morphology and plasticity through actin. RhoA activates the rho-associated protein kinase (ROCK) isoforms 1 and 2. ROCK1 then regulates actin motility and dendritic spine length through phosphorylation of myosin light chain (MLC) and inhibition of myosin light chain phosphatase (MLCP). Additionally, ROCK2 activates LIM kinase (LIMK), which inhibits cofilin. Both Rac1 and Cdc42 activate p21-activated kinase (PAK), which also activates LIMK. Active cofilin normally depolymerizes actin; thus, inactivation by LIMK reduces actin depolymerization and is a mechanism that regulates dendritic spine maintenance. Rac1 also activates the Wiskott-Aldrich syndrome protein family verprolin homologous protein (WAVE1) and Cdc42 activates the neuronal Wiskott-Aldrich syndrome protein (N-WASP), both of which promote actin polymerization and regulate dendritic spine maintenance through the actin-related protein 2/3 complex (Arp2/3). Arrows indicate activation, bar-headed lines indicate inhibition. Asterisks (*) are used to denote actin regulatory proteins that are discussed as putative pharmacological targets in the subsection, “Targeting Rho Signaling to Promote Resilience.”

Figure 3.

Dendritic spine loss in mammalian aging and Alzheimer’s disease dementia. Humans, non-human primates, and rodents are known to exhibit age-related cognitive decline. Age-related neuron loss is not commonly observed; therefore cognitive decline in aging is likely driven by loss of dendritic spine density, including thin spine reduction in the prefrontal cortex. Alzheimer’s disease is a progressive neurodegenerative disorder that features dendritic spine loss in multiple brain regions, including the cortex and hippocampus.

Figure 4.

Dendritic spines and factors that influence cognitive resilience to Alzheimer’s disease pathology. A) Illustration of a pyramidal neuron and its dendrite in healthy aging. B) Illustration of a pyramidal neuron surrounded by amyloid-β plaques and its dendrite with spine loss in Alzheimer’s disease dementia. C) Illustration of a pyramidal neuron surrounded by amyloid-β plaques and its dendrite that exhibits spine preservation and elongation in cognitive resilience to Alzheimer’s disease pathology. D) Factors that may contribute to cognitive resilience to Alzheimer’s disease pathology include exercise, mental activities, and transcription of post-synaptic density genes. These factors likely support maintenance of spine density and promote structural plasticity of dendritic spine morphology.