The β-amyloid (Aβ) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer’s disease (AD). Aβ is produced through sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Aβ generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD.

The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer's disease (AD). Muscarinic acetylcholine receptors (mAChRs) mediate acetylcholine-induced neurotransmission and five mAChR subtypes (M1-M5) have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists for AD treatment.Keywords: agonist; Alzheimer's disease; amyloid; cholinergic hypofunction; M1 muscarinic acetylcholine receptor; tau IntroductionAlzheimer's disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy [1,2] . Senile plaques and NFTs are major pathological hallmarks of AD in the brain. Senile plaques consist of deposits of small peptides called β-amyloid (Aβ). Multiple lines of evidence suggest that the overproduction/ aggregation of neurotoxic Aβ in vulnerable brain regions is the primary cause of AD [3][4][5][6] . NFTs are formed by accumulation of hyperphosphorylated tau protein [7, 8] . Tau is a microtubule-binding protein whose function is to stabilize microtubules and facilitate fast axonal transport. Once highly phosphorylated, tau dissociates from microtubules and is prone to aggregate, forming paired helical fi laments that aggregate into NFTs [9, 10] .The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine abnormalities; and (5) reduction in nAChR levels [11][12][13][14][15][16][17][18][19] .Recent evidence indicates that cholinergic hypofunction is closely linked to Aβ and tau pathologies [20] . As a major receptor group for ACh, mAChRs have also been implicated in the pathophysiology of AD. In the present review, we focus on M1 mAChR, the dominant mAChR subtype involved in learning and memory, and discuss its involvement in AD.Neurosci Bull April 1, 2014, 30(2): 295-307 296Overview of the mAChR Family m A C h R s a r e s e v e n -t r a n s m e m b r a n e G -p r o t e i ncoupled receptors. Upon binding to the endogenous neurotransmitter ACh, mAChRs couple to G proteins to transduct signals [21][22][23] . So far, fi ve mAChR subtypes (M1-M5) have been identifi ed and are divided into two categories based on the manner of signal transduction: M1, M3, and M5 subtypes preferentially interact with the G q/11 family of G proteins, activating phospholipase C and mobilizing intracellular calcium, while M2 and M4 subtypes couple to the G o/i family, inhibiting adenylate cyclases and reducing intracel...

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Polymer porous microspheres with large specific surface areas and good fluidity have promising important applications in the biomedical field. However, controllable fabrication of porous microspheres with precise size, morphology, and pore structure is still a challenge, and phase separation caused by the instability of the emulsion is the main factor affecting the precise preparation of porous microspheres. Herein, a method combining the iso-density emulsion (IDE) template and microfluidics was proposed to realize the controllable preparation of polymer porous microspheres. The IDE exhibited excellent stability with minimal phase separation within 4 h, thus showing potential advantages in the large-scale preparation of porous microspheres. With the IDE template combined microfluidics technique and the use of a customized amphoteric copolymer, PEG-b-polycaprolactone, polycaprolactone (PCL) porous microspheres with porosity higher than 90% were successfully prepared. Afterwards, the main factors, including polymer concentration, water–oil ratio and homogenization time were investigated to regulate the pore structure of microspheres, and microspheres with different pore sizes (1–30 μm) were obtained. PCL porous microspheres exhibited comparable cell viability relative to the control group and good potential as cell microcarriers after surface modification with polydopamine. The modified PCL porous microspheres implanted subcutaneously in rats underwent rapid in vivo degradation and tissue ingrowth. Overall, this study demonstrated an efficient strategy for the precise preparation of porous microspheres and investigated the potential of the as-prepared PCL porous microspheres as cell microcarriers and micro-scaffolds.