Danish and British dementia ITM2b/BRI2 mutations reduce BRI2 protein stability and impair glutamatergic synaptic transmission

Abstract

Mutations in Integral membrane protein 2B (ITM2b/BRI2) gene causes familial British and Danish dementia (FBD and FDD), autosomal dominant disorders characterized by progressive cognitive deterioration. Two pathogenic mechanisms, which may not be mutually exclusive, have been proposed for FDD and FBD: 1) loss of BRI2 function; 2) accumulation of amyloidogenic mutant BRI2-derived peptides, but the mechanistic details remain unclear. We have previously reported a physiological role of BRI2 in excitatory synaptic transmission at both presynaptic termini and postsynaptic termini. To test whether pathogenic ITM2b mutations affect these physiological BRI2 functions, we analyzed glutamatergic transmission in FDD and FBD knock-in mice, which carry pathogenic FDD and FBD mutations into the mouse endogenous Itm2b gene. We show that in both mutant lines, spontaneous glutamate release and AMPAR-mediated responses are decreased, while short-term synaptic facilitation is increased, effects similar to those observed in Itm2bKO mice. In vivo and in vitro studies show that both pathogenic mutations alter maturation of BRI2 resulting in reduced levels of functional mature BRI2 protein at synapses. Collectively, the data show that FDD and FBD mutations cause a reduction of BRI2 levels and function at synapses, which results in reduced glutamatergic transmission. Notably, other genes mutated in Familial dementia, such as APP, PSEN1/PSEN2, are implicated in glutamatergic synaptic transmission, a function that is altered by pathogenic mutations. Thus, defects in excitatory neurotransmitter release may represent a general and convergent mechanism leading to neurodegeneration. Targeting these dysfunction may offer a unique disease modifying method of therapeutic intervention in neurodegenerative disorders.

Familial Danish dementia young Knock-in rats expressing humanized APP and human Aβ show impaired pre and postsynaptic glutamatergic transmission

“…To explore early dysfunctions that may underlie initial mechanisms leading to dementia, we studied young KI rats carrying the Itm2b D Familial Danish dementia mutation. Consistent with the findings in Itm2b D/D mouse KIs (41), we found that Bri2-ADan maturation is altered and accumulates in Itm2b D/D primary neurons (Figure 2). Analysis of APP metabolism in peri-adolescent Itm2b D Ki rats (Figure 3 and 4) only showed subtle but significant changes in Aβ42 and Aβ43 steady-state levels, which were slightly increased and decreased, respectively (Figure 3).…”

“…Bri2 modulates glutamatergic synaptic transmission at both pre- and post-synaptic termini of Schaeffer-collateral pathway (SC)-CA3>CA1 synapses (47). This function is compromised in both adult Itm2b D and Itm2b B KI mice (41). Here, analyzed glutamatergic transmission at SC-CA3>CA1 synapses in young peri-adolescent Itm2b D male and female rats.…”

“…Finally, we examined the effect of the pathogenic Danish mutation on paired-pulse facilitation (PPF). PPF is a form of short-term synaptic plasticity that is in part determined by changes in P r of glutamatergic synaptic vesicles (48)(41). Facilitation at both 50ms and 200ms interstimulus interval (ISI), was significantly increased in Itm2b D/D (Figure 5I).…”

“…We have previously shown that the Danish and British ITM2b mutations lead to reduced glutamatergic neurotransmitter release and AMPAR-mediated responses in adult Itm2b B and Itm2b D mice (41). These reductions are like those seen in adult Itm2b knock-out mice (41,47). Interestingly, we detected identical, gene dosage-dependent, pre-and post-synaptic glutamatergic transmission changes in the SC pathway of peri-adolescent Itm2b D rats (Figure 5).…”

The Neuroprotective Effect of Tea Polyphenols on the Regulation of Intestinal Flora

“…Even more interesting is tea extract can block the reduction of TH, an enzyme that catalyzes tyrosine to L-dihydroxyphenylalanine (L-DOPA) in the dopamine biosynthesis pathway, finally preventing the death of dopaminergic neurons [ 125 ]. It is known that Glutamic acid (Glu) is one of the most important endogenous excitatory neurotransmitters; its excessive release will produce neurotoxicity, which is closely related to dementia, depression, and other diseases [ 126 ]. In the organotypic culture of the motor neuronal spinal cord in rats, EGCG was observed to block the Glu excitotoxicity induced by threonine-hydroxyapatite (THA) and regulate the level of Glu in cells.…”