Agonistic Autoantibodies to the α₁‐Adrenergic Receptor and the β₂‐Adrenergic Receptor in Alzheimer’s and Vascular Dementia

Abstract

Although primary causes of Alzheimer’s and vascular dementia are unknown, the importance of preceding vascular lesions is widely accepted. Furthermore, there is strong evidence for the involvement of autoimmune mechanisms. Here, we report the presence of agonistic autoantibodies directed at adrenergic receptors in the circulation of patients with mild to moderate Alzheimer’s and vascular dementia. In 59% of these patients, agonistic autoantibodies against the α1‐adrenergic receptor and the β2‐adrenergic receptor were identified. The majority of positive patients (66%) contained both types of autoantibodies in combination. In a control group of patients with neurological impairments others than Alzheimer’s and vascular dementia, only 17% were found to harbour these autoantibodies. The autoantibodies to the α1‐adrenergic receptor interacted preferably with the extracellular loop1 of the receptor. They were further studied in IgG preparations from the column regenerate of a patient who underwent immunoadsorption. The α1‐adrenergic receptor autoantibodies specifically bound to the extracellular loop1 peptide of the receptor with an apparent EC50 value of 30 nm. They mobilized intracellular calcium in a clonal cell line expressing the human form of the α1‐adrenergic receptor. Our data support the notion that autoimmune mechanisms play a significant role in the pathogenesis of Alzheimer’s and vascular dementia. We suggest that agonistic autoantibodies to the α1‐adrenergic and the β2‐adrenergic receptor may contribute to vascular lesions and increased plaque formation.

Antibodies to the α1-Adrenergic Receptor Cause Vascular Impairments in Rat Brain as Demonstrated by Magnetic Resonance Angiography

“…Dementia of the vascular and the Alzheimer’s type are difficult to discriminate, and typically they develop coincidentally. Recently we identified autoantibodies predominantly directed at the α 1 -AR in the circulation of patients with Alzheimer’s/vascular dementia [22]. The mechanisms underlying Alzheimer’s dementia are still a matter of dispute.…”

Biomarkers for the Early Detection and Progression of Alzheimer's Disease

“…The use of protein, peptides, and even peptoid arrays has led to the identification of autoantibodies specific to patients with AD. Autoantibodies against targets involved in synaptic activity, including neurotransmitters and receptors, are associated with cognitive decline, suggesting their use as signals of brain malfunction [262][263][264][265][266][267][268][269][270][271] (Table 1). With respect to inflammation, the relationship between neurodegeneration and autoimmunity was recently genetically confirmed in an epidemiological study where specific single-nucleotide polymorphisms in TREM2 (triggering receptor expressed on myeloid cells 2) and complement factors were shown to overlap between AD and immune diseases [272].…”

Autoantibodies Toward the Angiotensin 2 Type 1 Receptor: A Novel Autoantibody in Alzheimer’s Disease

“…These risk factors are known to be associated with agonist antibodies to key G protein-coupled receptors (GPCR) of the vasculature and autonomic nervous system, such as alpha 1 adrenoceptors (␣ 1 -AR), angiotensin 2 type 1 receptors (AT1R), beta 1 adrenoceptors (␤ 1 -AR), M2 muscarinic receptors (M 2 -MR), and endothelin-1-type A receptors (ET1A) [6][7][8][9][10]. Anti-GPCR antibodies such as anti-␤ 2 -AR and anti-␣ 1 -AR were recently found to be associated with AD and vascular dementia [11].…”