Abstract
Tau cleavage plays a crucial role in the onset and progression of Alzheimer’s Disease (AD), a widespread neurodegenerative disease whose incidence is expected to increase in the next years. While genetic and familial forms of AD (fAD) occurring early in life represent less than 1%, the sporadic and late-onset ones (sAD) are the most common, with ageing being an important risk factor. Intracerebroventricular (ICV) infusion of streptozotocin (STZ)—a compound used in the systemic induction of diabetes due to its ability to damage the pancreatic β cells and to induce insulin resistance—mimics in rodents several behavioral, molecular and histopathological hallmarks of sAD, including memory/learning disturbance, amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress and brain glucose hypometabolism. We have demonstrated that pathological truncation of tau at its N-terminal domain occurs into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice, and that it’s in vivo neutralization via intravenous (i.v.) administration of the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) is strongly neuroprotective. Here, we report the therapeutic efficacy of 12A12mAb in STZ-infused mice after 14 days (short-term immunization, STIR) and 21 days (long-term immunization regimen, LTIR) of i.v. delivery. A virtually complete recovery was detected after three weeks of 12A12mAb immunization in both novel object recognition test (NORT) and object place recognition task (OPRT). Consistently, three weeks of this immunization regimen relieved in hippocampi from ICV-STZ mice the AD-like up-regulation of amyloid precursor protein (APP), the tau hyperphosphorylation and neuroinflammation, likely due to modulation of the PI3K/AKT/GSK3-β axis and the AMP-activated protein kinase (AMPK) activities. Cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations occurring in STZ-infused mice were also strongly attenuated by 12A12mAb delivery. These results further strengthen the causal role of N-terminal tau cleavage in AD pathogenesis and indicate that its specific neutralization by non-invasive administration of 12A12mAb can be a therapeutic option for both fAD and sAD patients, as well as for those showing type 2 diabetes as a comorbidity.
Highlights
Alzheimer’s Disease (AD), the leading cause of dementia, involves genetic, environmental and metabolic factors, including alterations in brain insulin signaling and glucose metabolism, which occur several years before the clinical symptoms become evident [1,2,3].Amyloid-based models rely on the use of transgenic animals for the expression of mutations linked to familial forms of AD in the causative genes for amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2)
The main goals of this study were to test whether: (i) N-terminal tau cleavage occurred in intracerebroventricular administration of streptozotocin (ICV-STZ) preclinical model of sporadic forms (sAD); (ii) 12A12mAb delivery exerted an in vivo beneficial action on the cognitive and neurochemical and neuropathological hallmarks associated with animals’ AD phenotype
The assessment of cognitive deficits was scheduled in two separate time points, as follows: (i) 12–13 days after STZ infusion, mice were evaluated in the novel object recognition test (NORT) (Figure 2A,B), and 14–15 days after STZ infusion the same animals were assessed in the object place recognition task (OPRT) (Figure 2C,D); (ii) 21–22 days after STZ infusion, mice were evaluated in the NORT (Figure 3A,B) and
Summary
Amyloid-based models rely on the use of transgenic animals for the expression of mutations linked to familial forms of AD (fAD) in the causative genes for amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) These in vivo paradigms are valuable tools to study the molecular mechanisms underlying the AD etiopathogenesis, they do not replicate all aspects of disease’s neuropathology seen in human patients and are quite dissimilar from the most common sporadic forms (sAD). Numerous studies have reported that the human diabetic brain exhibits neuroinflammation, mitochondrial dysfunction, oxidative stress resulting in hippocampal vulnerability and synaptic damage [8,9,10] In this context, intracerebroventricular (ICV) infusion(s) of streptozotocin (STZ), a diabetogenic compound inducing in a laboratory animal a systemic resistance to insulin, can mimic some pathological aspects observed in brain of sAD subjects. The induction of insulin-resistant brain state following ICVSTZ further exacerbates the biochemical, immunohistochemical and behavioral hallmarks in two different models of hereditary AD, such as Tg2576 (APPKM670/671NL Swedish mutation) [35] and 3xTg (APP Swedish, MAPT P301L, and PSEN1 M146V) [36] mice
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