GABAergic Deafferentation Hypothesis of Brain Aging and Alzheimer’s Disease Revisited

Abstract

Considering the mechanisms responsible for age- and Alzheimer’s disease (AD)-related neuronal degeneration, little attention was paid to the opposing relationships between the energy-rich phosphates, mainly the availability of the adenosine triphosphate (ATP), and the activity of the glutamic acid decarboxylase (GAD), the rate-limiting enzyme synthesizing the γ-amino butyric acid (GABA). Here, it is postulated that in all neuronal phenotypes the declining ATP-mediated negative control of GABA synthesis gradually declines and results in age- and AD-related increases of GABA synthesis. The Ca²⁺-independent carrier-mediated GABA release interferes with Ca²⁺-dependent exocytotic release of all transmitter-modulators, because the interstitial (ambient) GABA acts on axonal preterminal and terminal varicosities endowed with depolarizing GABA_A-benzodiazepine receptors; this makes GABA the “executor” of virtually all age- and AD-related neurodegenerative processes. Such a role of GABA is diametrically opposite to that in the perinatal phase, when the carrier-mediated GABA release, acting on GABA_A/chloride ionophore receptors, positively controls chemotactic migration of neuronal precursor cells, has trophic actions and initiates synaptogenesis, thereby enabling retrograde axonal transport of target produced factors that trigger differentiation of neuronal phenotypes. However, with advancing age, and prematurely in AD, the declining mitochondrial ATP synthesis unleashes GABA synthesis, and its carrier-mediated release blocks Ca²⁺-dependent exocytotic release of all transmitter-modulators, leading to dystrophy of chronically depolarized axon terminals and block of retrograde transport of target-produced trophins, causing “starvation” and death of neuronal somata. The above scenario is consistent with the following observations: 1) a 10-month daily administration to aging rats of the GABA-chloride ionophore antagonist, pentylenetetrazol, or of the BDZ antagonist, flumazenil (FL), each forestalls the age-related decline in cognitive functions and losses of hippocampal neurons; 2) the brains of aging rats, relative to young animals, and the postmortem brains of AD patients, relative to age-matched controls, show up to twofold increases in GABA synthesis; 3) the aging humans and those showing symptoms of AD, as well as the aging nonhuman primates and rodents—all show in the forebrain dystrophic axonal varicosities, losses of transmitter vesicles, and swollen mitochondria. These markers, currently regarded as the earliest signs of aging and AD, can be reproduced in vitro cell cultures by 1 μM GABA; the development of these markers can be prevented by substituting Cl⁻ with SO₄²⁻; 4) the extrasynaptic GABA suppresses the membrane Na⁺, K⁺-ATPase and ion pumping, while the resulting depolarization of soma-dendrites relieves the “protective” voltage-dependent Mg²⁺ control of the N-methyl-d-aspartate (NMDA) channels, thereby enabling Ca²⁺-dependent persistent toxic actions of the excitatory amino acids (EAA); and 5) in whole-cell patch-clamp recording from neurons of aging rats, relative to young rats, the application of 3 μM GABA, causes twofold increases in the whole-cell membrane Cl⁻ conductances and a loss of the physiologically important neuronal ability to desensitize to repeated GABA applications. These age-related alterations in neuronal membrane functions are amplified by 150% in the presence of agonists of BDZ recognition sites located on GABA receptor. The GABA deafferentation hypothesis also accounts for the age- and AD-related degeneration in the forebrain ascending cholinergic, glutamatergic, and the ascending mesencephalic monoaminergic system, despite that the latter, to foster the distribution-utilization of locally produced trophins, evolved syncytium-like connectivities among neuronal somata, axon collaterals, and dendrites, to bidirectionally transport trophins. In such a syncytium, the unmyelinated fine axon collaterals and dendrites are endowed with GABA_A–BDZ receptors whose activation causes a depolarization block, as indicated by recording from unmyelinated axon preterminal and terminal varicosities. The increases of GABA synthesis in the brain stem of aging rats and AD patients result in up to twofold steady GABA elevation, relative to young rats or age-matched human controls, respectively. Thus, GABA and BDZ agonist ligands may block the paracrine-autocrine transport/utilization of trophins. Once initiated, the age- and AD-related deleterious GABA actions may be expected to become a self-reinforcing process, because GABAergic depolarization and dystrophy of axon terminal mitochondria would block ATP production, maximize GAD activity, and GABA synthesis and release. The overview of FL’s unique profile of metabotropic and nootropic actions, apparently contingent on its antagonism of endogenous BDZ ligands, both in humans and animals, suggests that FL has a promising clinical potential.