A Novel Concept is Needed for Combating Alzheimer's Disease and NeuroHIV

Abstract

Both Alzheimer’s disease (AD) and HIV-associated neurocognitive disorders (HAND) could progress to dementia, a severe consequence of neurodegenerative diseases. Cumulating evidence suggests that the β-amyloid (Aβ) theory, currently thought to be the predominant mechanism underlying AD and AD-related dementia (ADRD), needs re-evaluation, considering all treatments and new drug trials based upon this theory have been unsuccessful. Similar intention for treating HAND, including HIV-associated dementia (HAD), has also failed. Thus, novel theory, hypothesis, and therapeutic strategies are desperately needed for future study and effective treatments of AD/ADRD and HAND. There are numerous potential upstream mechanisms that may cause AD and/or HAND; but it is unrealistic to identify all of them. However, it is realistic and feasible to intervene the downstream mechanism of these two devastating neurodegenerative diseases by blocking the final common path to neurotoxicity mediated by overactivation of NMDA receptors (NMDARs) and voltage-gated calcium channels (VGCCs). Such a combined pharmacological intervention will likely ameliorate neuronal Ca 2+ homeostasis by diminishing overactivated NMDAR and VGCC-mediated Ca 2+ dysregulation (i.e., by reducing excessive Ca 2+ influx and intracellular levels, [Ca 2+ ]in)-induced hyperactivity, injury, and death of neurons in the critical brain regions that regulate neurocognition in the context of AD/ADRD or HAND, especially during aging. Here we present a novel theoretical concept, hypothesis, and working model for switching the battlefield from searching-and-fighting the original mechanism that may cause AD or HAND, to abolishing AD- and neuroHIV-induced neurotoxicity mediated by NMDAR and VGCC over activation, which may ultimately improve the therapeutic strategies for treating AD and HAND.

Hyperactivity of medial prefrontal cortex pyramidal neurons occurs in a mouse model of early-stage Alzheimer’s disease without β-amyloid accumulation

“…Previous findings from early-stage AD study ( Buckner et al, 2005 ; Palmqvist et al, 2017 ; Hu, 2020 ; Zhang et al, 2021 ) align with our perspective ( Hu, 2020 ) but is conflicting with the Aβ theory. It therefore motivates us to advance our understanding of neuron dysfunction in the brain regions susceptible to Aβ in early-stage AD.…”

“…The accumulation of β -Amyloid (Aβ) has long been considered a key hallmark of Alzheimer’s disease (AD) ( LaFerla and Oddo, 2005 ; Querfurth and LaFerla, 2010 ) and linked to neuronal Ca 2+ imbalance ( Xie, 2004 ; Mattson, 2007 ; Small et al, 2009 ; Yu et al, 2009 ; Tong et al, 2018 ). However, its exact role in the development of AD is still debated ( Hu, 2020 ; Zhang et al, 2021 ). Previous studies shows that Aβ levels increase in the brains of AD patients and decrease in the cerebrospinal fluid (CSF) of some early-stage AD patients before the formation of Aβ plaques and the onset of symptoms ( Buckner et al, 2005 ; Palmqvist et al, 2017 ).…”

“…There is a lack of scientific knowledge regarding how AD alters the functional activity of live neurons in the PFC and HIPP in the brain, and whether Aβ causes such neuronal dysfunction during AD progression and aging. Previous studies suggest that Aβ not only impacts NMDA receptors (NMDARs) and voltage-gated L-type Ca 2+ channels (L-channels) ( Mattson, 2007 ; Hu, 2020 ), but also creates unconventional but functional Ca 2+ -permeable channels that have similar structure and function of the L-channel ( Arispe et al, 1993 ; Pollard et al, 1993 ; Abramov et al, 2004 ; Lal et al, 2007 ; Shirwany et al, 2007 ; Itkin et al, 2011 ). These dysfunctions lead to neurotoxicity ( Xie, 2004 ; Mattson, 2007 ; Small et al, 2009 ; Yu et al, 2009 ; Tong et al, 2018 ) in glutamatergic pyramidal neurons ( Li et al, 2010 ; Kim and Rhim, 2011 ), which make up 80%–90% of neurons in the PFC and HIPP ( Gabbott et al, 1997 ; Yuste, 2005 ).…”

“…However, the extent to which Aβ affects the functional activity of live PFC neurons is still unclear, especially in the different stages of AD. The role of L-channel dysfunction and NMDAR overactivation ( Xie, 2004 ; Mattson, 2007 ; Small et al, 2009 ; Yu et al, 2009 ; Tong et al, 2018 ), in causing intracellular Ca 2+ dyshomeostasis, neurotoxicity, and therefore potentially contributing to AD neuropathology is also not well understood ( Lal et al, 2007 ; Mattson, 2007 ; Shirwany et al, 2007 ; Itkin et al, 2011 ; Hu, 2016 ; Hu, 2020 ).…”

“…The earliest accumulation of Aβ in the brain occurs primarily in the orbital/medial PFC (o/mPFC) and HIPP, brain regions that are anatomically connected and functionally interplay to regulate neurocognition Buckner et al, 2005 ; Palmqvist et al, 2017 ). However, despite extensive research focusing on the neuropathology of the HIPP, the mPFC, another crucial regulator of neurocognition, is understudied, and therefore, is of particular interest to us ( Hu, 2016 ; Hu, 2020 ).…”