Dysfunctional Bladder Morphology and Functional Impairments Are Identified in the Alzheimer’s Disease APP^{NL-G-F/NL-G-F} Murine Model

Article type: Research Article

Authors: Ge, Yingying^{a; 1} | AlObaidi, Alya S.^{a; b; 1} | Kuchel, George A.^b | Bartley, Jenna M.^{b; c} | Smith, Phillip P.^{a; b; †} | He, Wanxia^a | Hu, Xiangyou^{a; *}

Affiliations: [a] Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA | [b] Center on Aging, UConn Health, Farmington, CT, USA | [c] Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, USA

Correspondence: [*] Correspondence to: Xiangyou Hu, MD, PhD, Department of Neuroscience, University of Connecticut School of Medicine, 263 Farmington Ave., Farmington, CT 06030-3401, USA. Tel.: +1 860 679 6249; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [†] Deceased.

Abstract: Background:While symptoms related to lower urinary tract dysfunction (LUTD) are common in individuals with Alzheimer’s disease (AD), pathophysiological links between AD and LUTD remain unclear. Objective:This study aimed to investigate whether AD neuropathology would cause autonomic dysfunction along the spinal cord-bladder axis, which could result in alterations in bladder muscle kinetics. Methods:We utilized APPNL-G-F/NL-G-F knock-in (APP KI) and APPwt/wt (wild-type) mice at two different ages, 4- and 10-month-old, to investigate how AD impacts bladder tissue function by immunohistochemistry, western blotting, and pharmacomyography. Results:We showed that the mucosal layer partially separated from the detrusor in 10-month-old APP KI mouse bladders. Although there was no detectable amyloid deposition in the APP KI bladder, we found amyloid plaques in APP KI lumbar spinal cord. Further immunoblot analysis revealed that tyrosine hydroxylase protein levels were significantly reduced in both 4- and 10-month-old bladder tissues, suggesting reduction of norepinephrine synthesis in APP KI mouse bladders. In contrast, the level of β2 adrenergic receptor was increased in 4-month-old but not 10-month-old APP KI bladders. In bladder strips, the adrenergic agonist isoproterenol induced increased relaxation in 4- but not 10-month-old APP KI bladders. With 10 Hz electrical field stimulation, 10-month-old APP KI bladder strips were more responsive than wild-type controls, with no differences observed in 4-month-old APP KI bladders. Conclusions:APP KI mice exhibit LUTD, which is likely arising from amyloid pathology in the spinal cord, and results in maturational declines in presynaptic activity combined with compensatory postsynaptic upregulation.

Keywords: Alzheimer’s disease, amyloid plaque, bladder, bladder dysfunction, bladder pharmacomyography, lower urinary tract dysfunction, neurotransmitters

DOI: 10.3233/JAD-230547

Journal: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 395-408, 2024