Emerging pathways driving early synaptic pathology in Alzheimer's disease

Abstract

The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca2+ signaling disruptions, and focus on its role in driving synaptic deficits – which is the feature that does correlate with AD-associated memory loss. Excess Ca2+release from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IP3R and RyR, and the recent emphasis on RyR2. Consistent with ER Ca2+ mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca2+-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.

Dysregulation of neuronal calcium homeostasis in Alzheimer's disease – A therapeutic opportunity?

“…These results consistent with reports that dantrolene exerted beneficial effects in several AD mouse models [64–66] and suggested that blocking RyanR is a viable therapeutic strategy. This idea is reviewed in depth by Dr. Grace Stutzmann and her colleagues in the accompanying review article [71]. …”

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

“…Our findings suggest that both Aβ 42  PUMA might separately or jointly damage  m . Taken together, these data indicate that Neuronal calcium (Ca 2+ ) dyshomeostasis has been proposed to play a crucial role in AD disease progression [68]. However, the mechanisms of Ca 2+ dysregulation are not clear.…”

[P3–102]: Genetic Risk for Schizophrenia and Psychosis in Alzheimer Disease

“…[88][89][90] How reductions in voltage-dependent calcium channel function may further increase AD+P risk is not known, however, impairments of intracellular Ca 2+ homeostasis are present in AD, and can contribute to synaptic dysfunction and cognitive impairments. 91 We recently estimated the annual incidence of psychosis in AD at 10%. 40 Thus there is an opportunity to intervene prior to psychosis onset if individual predictors can be identified.…”