GRK5 deficiency leads to early Alzheimer-like pathology and working memory impairment.
G-protein coupled receptor kinase-5 (GRK5) deficiency has been linked to early Alzheimer's disease in humans and mouse models of the disease. To determine potential roles of GRK5 in the disease pathogenesis, the GRK5 knockout mouse was evaluated at pathological and behavioral levels. We found that these mice displayed an age-dependent increase in hippocampal axonal defects characterized by clusters of axonal swellings that accumulated abnormal amounts of molecular motor proteins, microtubule-associated proteins, intracellular beta-amyloid, and subcellular organelles. In severe cases, extracellular beta-amyloid fibrillar deposits were occasionally observed, along with degenerating axonal components, and were tightly surrounded by reactive astrocytes. Moreover, significant loss of synaptic proteins and early signs of cholinoceptive neurodegeneration were evident in the hippocampus as well. Consistent with the moderate level of pathologic change, aged GRK5 knockout mice displayed selective working memory impairment, with other cognitive domains unaffected. Taken together, these findings not only strongly support an important role of GRK5 deficiency in early Alzheimer's pathogenesis, but also promote the GRK5 knockout mouse as an additional model for early Alzheimer-related studies.
Suo
Zhiming
Z
Laboratory for Alzheimer's Disease & Aging Research, Veterans Affairs Medical Center, Kansas City, MO 64128, USA. zsuo@kumc.edu
Cox
April A
AA
Bartelli
Nicholas
N
Rasul
Imtiaz
I
Festoff
Barry W
BW
Premont
Richard T
RT
Arendash
Gary W
GW
D000544:Alzheimer Disease / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000172:deficiency*; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology*; D008569:Memory Disorders / Q000473:pathology* / Q000503:physiopathology*; D008570:Memory, Short-Term; D051379:Mice; D018345:Mice, Knockout
D054774:G-Protein-Coupled Receptor Kinase 5; C517895:Grk5 protein, mouse