6.1.2. Inositol Use for Brain Insulin Resistance in Alzheimer's Disease

Insulin resistance has emerged as one cause–effect of AD [205]. Recent studies have shown that cognitive impairment and AD progression are related to a dysfunction in insulin signaling in the hippocampus and frontal cortex. Postmortem analysis of human hippocampal tissue shows a correlation between high serine-inhibitory phosphorylation of IRS1 and oligomeric Aβ plaques, which were negatively associated with working memory and episodic memory [206]. The same study observed that GSK3-β activity was correlated with insulin resistance and tau hyperphosphorylation [206]. Further studies have shown that early hyperactivation of insulin signaling may cause negative feedback mediated by mTOR and decreased biliverdin-A reductase (BVR-A) activity, an oxidative stress-sensitive antioxidant enzyme and second messenger in insulin signaling, controlling IRS1 and Akt serine phosphorylation [207,208]. Brain insulin resistance and increased oxidative stress lead to overall carbonyl and peroxynitrite protein modifications, leading to signaling dysfunction and a decrease in cognitive performance [209]. An in vitro study showed that the accumulation of ADDLs

caused a loss of surface IRs, and ADDL-induced oxidative stress and synaptic spine deterioration could be completely prevented by insulin treatment [209].

Since insulin resistance is an accepted contributor to a worsening AD condition, some strategies have been designed in order to restore insulin signaling in the brain. A proposed strategy is the use of intranasal insulin [210], as it has been proven to be effective at restoring cognitive function, decreasing Aβ aggregation, tau hyperphosphorylation, and nitrosative stress in a 3xTg mouse model of AD [211]. Intranasal insulin has been part of clinical trials, with minimal safety concerns reported so far [212]. Moreover, insulin is a short-life acting molecule, and some derivatives are currently under development [212,213]. Although it is beyond the scope of this review to focus on the insulin molecule itself as a potential treatment for brain insulin resistance-related pathologies, this short summary paves the way for the use of naturally occurring insulin-mimetic compounds, the safety of which has been tested in humans.

The potent stimulatory effect of DCI on insulin signaling is highly likely to contribute to an insulin neuroprotective effect on AD. DCI is effectively transported through the blood–brain barrier and stimulates insulin signaling, as seen in the hypothalamus [214]. An in vitro study showed that DCI, its methyl derivative DPIN, and DCI-GPI INS-2 increased IR autophosphorylation at a dose of 100 μM in primary rat hippocampal neurons [107]. Moreover, the same dose of DCI potentiated insulin-mediated inhibition of ADDL binding to neuron spines and neurites and ADDL-induced synapse damage to neurons [107]. This effect was not observed for MI and was suppressed after addition to PI3K, ERKm, and IGF1R inhibitors, blocking insulin DCI-potentiated signaling [107]. Although these results suggest inositols such as DCI or DPIN are an effective treatment for preserving insulin-deficient signaling in the brain, there are few data on the use of insulin-mimetic inositols in vivo. This is likely due to biased use of SI amongst all inositol derivatives, given its direct interaction with Aβ aggregates.

The use of strong insulin-sensitizers like DCI and their derivatives could serve as an alternative treatment, based on compounds easily obtained from natural sources, whose use in high doses in humans has proven to be safe and effective in other pathologies caused by insulin resistance [27,215]. Moreover, increasing evidence suggesting that peripheral type 2 diabetes exacerbates AD development raises the interest for combinational therapies. The possible protective role of inositols in T2D and AD comorbidity will be summarized in the next section.

6.1.3. Unhealthy Dietary Habits and Microvascular Damage in Alzheimer's Disease: Preventive Inositol Supplementation

Since brain insulin resistance contributes to AD development, increasing evidence suggests that peripheral type 2 diabetes mellitus (T2DM) may overlap and exacerbate AD-related cognitive impairment, neuroinflammation, oxidative stress, Aβ aggregation, tau hyperphosphorylation, and synaptic dysfunction [216–218]. A meta-analysis has shown a 56% increased risk of AD in diabetic patients, and a high prevalence of mixed pathologies [219].

A high fat diet in experimental models, leading to development of T2DM, produces Aβ deposition through altered mechanisms of autophagy and apoptosis, as well as neuroinflammation though alteration in the metabolism and the production of ROS and pro-inflammatory mediators [220–223]. Middle-aged patients with insulin resistance share common features with AD as the uncoupling of macrovascular blood flow and microvascular perfusion, which is likely due to coupling through the metabolic alterations derived from metabolic shifts induced by the oxidation of fatty acids [224,225]. In addition, high fat diets can modify microbiota compositions, altering the reaction of the intestinal immune barrier. These events might result in changes in circulating levels of pro-inflammatory mediators (cytokines, chemokines, endotoxin) produced at the intestinal levels [226].

The concomitant combination of insulin resistance, a chronic pro-inflammatory state, oxidative stress, and vascular endothelial dysfunction might directly promote an adverse environment for neuronal survival in the context of AD, thus worsening AD-related features. As we have previously described, inositols have been effectively used for treatment of insulin resistance-related pathologies. Regarding insulin-based therapies in AD, the use of intranasal insulin has no cognitive benefits in prediabetic animals compared to non-diabetic animals [227].

In this perspective, the fact that inositols exert an insulin sensitizing effect, but also directly improve endothelial function and act as antioxidant molecules, suggests its use as a supplement in a preventive way. Although no publication exists on the use of Alzheimer's-associated inositols in the context of insulin resistance, some patents have covered this issue. Pasinetti showed that treatment with 100 mg/kg DPIN administered ad libitum in a Tg2576 mouse model of AD exposed to a high fat diet reduced Aβ levels in the hippocampus, neocortex, and serum through the restoration in the brain of insulin receptor signal transduction [204].

Because inositols are insulin-sensitizers that restore deficient insulin signaling without hyperactivation of insulin signaling, avoiding insulin side-effects, their preventive use as prophylactic agents has emerged as a powerful strategy to delay or lessen the impact of cognitive decline, protecting from synaptic dysfunction. Therefore, we suggest a combination of inositol supplementation with healthy dietary intervention, which is able to modulate microbial production of inositols like SI for the pre-treatment and treatment of AD pathology [228].
