The GRK2 Overexpression Is a Primary Hallmark of Mitochondrial Lesions during Early Alzheimer Disease

Abstract

Increasing evidence points to vascular damage as an early contributor to the development of two leading causes of age-associated dementia, namely Alzheimer disease (AD) and AD-like pathology such as stroke. This review focuses on the role of G protein-coupled receptor kinases (GRKs) as they relate to dementia and how the cardio and cerebrovasculature is involved in AD pathogenesis. The exploration of GRKs in AD pathogenesis may help bridge gaps in our understanding of the heart-brain connection in relation to neurovisceral damage and vascular complications of AD. The a priori basis for this inquiry stems from the fact that kinases of this family regulate numerous receptor functions in the brain, myocardium and elsewhere. The aim of this review is to discuss the finding of GRK2 overexpression in the context of early AD pathogenesis. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis through the cerebrovasculature. Finally, we synthesize this newer information in an attempt to put it into context with GRKs as regulators of cellular function, which makes these proteins potential diagnostic and therapeutic targets for future pharmacological intervention.

Figure 1

Subcellular localization of GRK2 immunoreactivity detected by using preembedding immunogold decoration in hippocampus of age-matched control (a, b) and AD brain (c, d). (a) and (b) The neuronal cell body from the age-matched control brain hippocampal tissue shows the presence of GRK2 containing gold particles (arrows) attached to the external membrane of partially damaged mitochondria. GRK2 immunopositive gold particles localized in the matrix of damaged mitochondria and Golgi cistern, X 30,000 and X 40,000, respectively, (a) and (b). (c) Hippocampal tissue from the AD brain shows that the neuronal cell body is characterized by the presence of large number of mitochondria-derived lysosomes (M) and disperse distribution of GRK2 positive gold particles (arrows), X 6,000. (d) Glial cell body from the AD brain tissue shows clusters of GRK2 immunoreactivity in the matrix of mitochondria derived-lysosomes (single arrow), X 20,000. Abbreviations: M Mitochondria; N cell nucleus, [reprinted with permission of Neurotoxicity Research [8]

Figure 2

The ultrastructural localization of GRK2 immunopositive gold particles in postmortem human AD (a) and age-matched control brain (b, c) tissues. (a) The GRK2: immunopositive containing gold particles in the matrix of perivascular pericytes (indicated by single thick arrows) but not in the cytoplasmic matrix of severely damaged vascular endothelium (EC), X 40,000. (b) and (c) The neurons close to perivascular regions show the presence of GRK2 containing gold particles in their matrix, where most gold particles were associated with the neurofibrillary tangle- (NFT-) like structures (arrows). However, the intact mitochondria (M) were free from GRK2-immunopositive gold particles, X 40,000, respectively, (b) and (c). (reprinted with permission of Neurotoxicity Research [8]).

Figure 3

Ultrastructural characteristics of GRK2: immunopositive gold particles from the rat brain in control (same-operated: a, b) and 2-vessel occlusion (2-VO; resp., c, d) experiments. (a) Clusters of GRK2: immunopositive gold particles in the cytoplasmic matrix of perivascular pericytes (arrows) but not in the vascular EC, X 20,000. (b) The presence of GRK2 immunopositive gold particles associated with the edematous portion of the perivascular pericytes cytoplasmic matrix (arrows). Intact, but not giant, mitochondria (M) are free from any GRK2-immunopositive positive gold particles, X 30,000. (c) The GRK2 containing positive gold particles was seen in the hippocampal tissues from rat exposed to 2-VO. The presence of GRK2 immunopositive gold particles was seen throughout the matrix of damaged perivascular pericytes (arrows), X 8,000. (d) Perivascular regions of this area from figure (c) under higher magnification display the presence of islands of GRK2-containing gold particles which are associates with the damaged regions of the cytoplasmic matrix (arrows). Nucleus (N) and intact mitochondria are from the GRK2 immunoreactivity, X 30,000. (reprinted with permission of Neurotoxicity Research [8]).

Figure 4

The subcellular features of the GRK2 immunoreactivity in the hippocampus of the rat subjected to 2-vessel occlusion. (a) Intact neurons show absence of any GRK2 immunopositive gold particles in their cytoplasmic matrix, X 15,000. (b) Neurons with the effect of chronic cellular hypoperfusion demonstrate the presence of a GRK2 overexpression (arrows) throughout the cell body, however, the intact mitochondria (M) were free from any GRK2 immunopositive gold particles, X 30,000. (c) “Hypoperfusion”-affected neuronal cell body show the presence of islands of GRK2 positive immunodecoration in the external membrane and in the matrix of damaged mitochondria and mitochondria-derived lysosomal structures (arrows), X 40,000. (d) Neurons with severe damage shows the presence of islands of GRK2 containing immunopositive gold particles that associated with the completely damaged (mitochondria-derived lysosomal structures) (arrows), but not with nondamaged mitochondria (intact and giant), X 40,000. (reprinted with permission of Neurotoxicity Research [8]).

Figure 5

The GRK2 immunoreactivity in rat brain hippocampal tissues was exposed to 2-vessel occlusion and determined by using preembedding immunogold cytochemistry techniques. (a) Subcellular determination of GRK2 in the neuronal cell body shows the presence of GRK2 immunopositive gold particles (arrows), which associates with the external membrane and the matrix of damaged but not intact mitochondria (M), X 40,000. (b) Neurons containing granular vacuolar degenerative structures show island of GRK2 immunopositive gold particles (single arrow), X 30,000. (c) The glial cell body shows overexpression of GRK2 immunoreactivity in the matrix of granular vacuolar degenerative structures (single arrow), X 50,000. (d) Neurofilament from the damaged neurons shows the presence of GRK2 immunopositive gold particles (single arrows), X 40,000 (reprinted with permission of Neurotoxicity Research [8]).

Figure 6

The role of GRK2 in AD showing the activation pathways and consequences of increased expression of GRK2 with the endothelium, brain, and mitochondria.