Cooperative interactions between neurotrophin receptors and CXCR4 regulate macrophage phenotype and susceptibility to activation by HIV.

Neural damage due to inflammatory activation of macrophages and microglia is a consequence of HIV infection that leads to cognitive dysfunction. The damage is due, in part, to the release of factors that impair neuronal function but the mechanisms that control their release are poorly understood. Previous studies have shown that mature nerve growth factor (NGF) binding to tropomyosin receptor kinase A (TrkA), and proNGF acting through the p75 neurotrophin receptor (p75) differentially control the phenotype of macrophages in response to HIV.

Rab35 and glucocorticoids regulate APP and BACE1 trafficking to modulate Aβ production.

Chronic stress and elevated glucocorticoids (GCs), the major stress hormones, are risk factors for Alzheimer's disease (AD) and promote AD pathomechanisms, including overproduction of toxic amyloid-β (Aβ) peptides and intraneuronal accumulation of hyperphosphorylated Tau protein. The latter is linked to downregulation of the small GTPase Rab35, which mediates Tau degradation via the endolysosomal pathway. Whether Rab35 is also involved in Aβ overproduction remains an open question.

Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology.

Despite considerable progress in the understanding of its neuropathology, Alzheimer's disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aβ) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound.

Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction.

Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear.