Jiang Ying, Sachdeva Kuldeep, Goulbourne Chris N, Berg Martin J, Peddy James, Stavrides Philip H, Pensalfini Anna, Pawlik Monika, Malampati Sandeep, Whyte Lauren, Basavarajappa Balapal S, Subbanna Shivakumar, Bleiwas Cynthia, Smiley John F, Mathews Paul M, Nixon Ralph A
Center for Dementia Research, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York 10962.
Department of Psychiatry, New York University Grossman School of Medicine, New York, New York 10016.
J Neurosci. 2025 Jul 16;45(29):e2331242025. doi: 10.1523/JNEUROSCI.2331-24.2025.
Endosomal system dysfunction within neurons is a prominent early feature of Alzheimer's disease (AD) pathology. Multiple AD risk factors are regulators of endocytosis and known to cause hyperactivity of the early endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption and cholinergic neurodegeneration. Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine binding domain, Leucine zipper motif (APPL1), an important rab5 effector protein and signaling molecule has been shown in vitro to interface between endosomal and neuronal dysfunction through a rab5-activating interaction with the BACE1-generated C-terminal fragment of amyloid precursor protein (APP-βCTF), a pathogenic APP fragment generated within endosomal compartments. To understand the contribution of APPL1 to AD-related endosomal dysfunction in vivo, we generated a transgenic mouse model overexpressing human APPL1 within neurons (Thy1-APPL1). Strongly supporting the important endosomal regulatory roles of APPL1 and their relevance to AD etiology, Thy1-APPL1 mice (both sexes) develop enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We demonstrated pathophysiological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), degeneration of large projection cholinergic neurons of the basal forebrain, and impaired hippocampal-dependent memory. Our evidence shows that neuronal APPL1 elevation modeling its functional increase in the AD brain induces a cascade of AD-related pathological effects within neurons, including early endosome anomalies, synaptic dysfunction, and selective neurodegeneration. Our in vivo model highlights the contributions of APPL1 to the pathobiology and neuronal consequences of early endosomal pathway disruption and its potential value as a therapeutic target.
神经元内的内体系统功能障碍是阿尔茨海默病（AD）病理的一个突出早期特征。多种AD风险因素是内吞作用的调节因子，已知会导致早期内体小GTP酶rab5的活性过高，从而导致神经元内体途径破坏和胆碱能神经变性。含普列克底物蛋白同源结构域、磷酸酪氨酸结合结构域、亮氨酸拉链基序的衔接蛋白（APPL1）是一种重要的rab5效应蛋白和信号分子，在体外已显示它通过与β-淀粉样前体蛋白（APP）经β-分泌酶1（BACE1）切割产生的C端片段（APP-βCTF）进行rab5激活相互作用，在内体功能障碍和神经元功能障碍之间起连接作用，APP-βCTF是在内体区室中产生的一种致病性APP片段。为了了解APPL1在体内对AD相关内体功能障碍的作用，我们构建了一个在神经元中过表达人APPL1的转基因小鼠模型（Thy1-APPL1）。Thy1-APPL1小鼠（雌雄均有）由于rab5激活增加，出现神经元早期内体增大和突触内吞作用增强，这有力地支持了APPL1重要的内体调节作用及其与AD病因的相关性。我们证明了APPL1过表达的病理生理后果，包括海马长时程增强（LTP）和长时程抑制（LTD）的功能变化、基底前脑大型投射胆碱能神经元的变性以及海马依赖性记忆受损。我们的证据表明，模拟其在AD大脑中功能增加的神经元APPL1升高会在神经元内引发一系列与AD相关的病理效应，包括早期内体异常、突触功能障碍和选择性神经变性。我们的体内模型突出了APPL1对早期内体途径破坏的病理生物学和神经元后果的作用及其作为治疗靶点的潜在价值。
