Telomere shortening reduces Alzheimer’s disease amyloid pathology in mice

Abstract

Alzheimer's disease is a neurodegenerative disorder of the elderly and advancing age is the major risk factor for Alzheimer's disease development. Telomere shortening represents one of the molecular causes of ageing that limits the proliferative capacity of cells, including neural stem cells. Studies on telomere lengths in patients with Alzheimer's disease have revealed contrary results and the functional role of telomere shortening on brain ageing and Alzheimer's disease is not known. Here, we have investigated the effects of telomere shortening on adult neurogenesis and Alzheimer's disease progression in mice. The study shows that aged telomerase knockout mice with short telomeres (G3Terc-/-) exhibit reduced dentate gyrus neurogenesis and loss of neurons in hippocampus and frontal cortex, associated with short-term memory deficit in comparison to mice with long telomere reserves (Terc+/+). In contrast, telomere shortening improved the spatial learning ability of ageing APP23 transgenic mice, a mouse model for Alzheimer's disease. Telomere shortening was also associated with an activation of microglia in ageing amyloid-free brain. However, in APP23 transgenic mice, telomere shortening reduced both amyloid plaque pathology and reactive microgliosis. Together, these results provide the first experimental evidence that telomere shortening, despite impairing adult neurogenesis and maintenance of post-mitotic neurons, can slow down the progression of amyloid plaque pathology in Alzheimer's disease, possibly involving telomere-dependent effects on microglia activation.

Enhanced microglial pro‐inflammatory response to lipopolysaccharide correlates with brain infiltration and blood–brain barrier dysregulation in a mouse model of telomere shortening

“…A study investigating the role of telomere shortening on plaque pathology using APP23 mice (a mouse model for Alzheimer's disease) crossed with telomerase knockout mice (mTerc −/− ) indicated that telomere shortening improved the spatial learning ability and decreased plaque load (Rolyan et al ., 2011). The study showed a change in morphology of G3 mTerc −/− microglia but did not display differences in expression of microglia proteins such as MHC II that are altered during activation.…”

Telomere Length and Aging

“…Alzheimer's is a neurodegenerative disease associated with aging (Rolyan et al, 2011). Currently, more than 35 million people around the world are effected, and this number is predicted to dramaticaly increase as life expectency is prolonged.…”

Telomere in Aging and Age-Related Diseases

“…(156,165) Although not immediately, telomere shortening in leukocytes and microglia can affect neuronal health by compromising the normal functions of these immune cells within the brain. (168,169) The roles of the immune system in the initiation and progression of Newcastle disease (ND) are being actively investigated. (170) Telomere shortening in immune cells, astrocytes and neurons could amplify oxidative stress-dependent senescence and secretion of proinflammatory mediators (senescence-associated secretory phenotype), results in diseases progression.…”