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Alzheimer’s disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 — a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses — in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins — including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) — and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aβ and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01143-1.

Most age-associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion-like process of template protein corruption or seeding. In fact, studies in FAD-based animal models show that Aβ deposition and cerebral amyloid angiopathy may be induced by intracerebral infusion of brain extracts from AD patients or from aged APP-transgenic mice. These studies have shown that the characteristic of both the seeding agent and the host influence the pathologic signature of the Aβ seeds. In this regard, the majority of the Aβ-seeding studies have been done in APP-transgenic animal models that overproduce APP and/or Aβ. However, it remains to be elucidated whether Aβ deposition can be induced by Aβ seeds in an animal model that does not overexpress APP and produces wild type human Aβ and if these aggregates are similar to the human condition. Here, we used an innovative animal model to better understand the amyloidogenic events that occur in the sporadic form of the disease. Our model, termed hAβ-KI, expresses wild-type human Aβ under the control of the endogenous mouse APP gene. Thus, amyloid seeds from AD patients (stage C for amyloid) from the Alzheimer’s Disease Research Center (ADRC) at UCI were administered into 7-8-month-old hAβ-KI and as positive controls 3xTg-AD mice were employed. Our findings demonstrated that amyloid seeds differentially occur in 3xTg-AD and hAb-KI mice and these aggregates are developed earlier in the familial model, 3xTg-AD mice. These results suggest that multiple factors such as the seed, recipient model and time are critical factors that can modulate the amyloid pathology onset and progression. Thus, more profound understanding these factors will provide key insight on how amyloid pathology progress in AD. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech.

The majority of Alzheimer’s disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules., Most instances of Alzheimer’s disease (AD) are sporadic or not associated with a particular mutation. Here, the authors develop knock-in mice that express wildtype human Aβ under control of the mouse App locus, which may have potential for modelling some aspects of sporadic late onset AD.